Oral Soluble Film and Multi-layered Film Including an Oral Soluble Film Layer

ABSTRACT

An oral soluble film contains at least one active agent. Alternatively, a multi-layered film includes a plurality of layers, at least one at least one of the plurality of layers being an oral soluble film layer containing at least one active agent. The oral soluble film may be made, e.g., by a method comprising providing a well of a predetermined size; depositing a film forming composition in the well; metering a predetermined amount of an active agent composition in the well separately from the film forming composition, the active agent composition being different than the film forming composition, the film forming composition and the active agent composition forming a single layer in the well; and drying the single layer in the well to form the oral soluble film containing the at least one active agent.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional application of U.S. application Ser.No. 16/703,992, filed Dec. 5, 2019, which is a continuation applicationof U.S. application Ser. No. 16/244,270 filed Jan. 10, 2019, nowabandoned, which is a continuation application of U.S. application Ser.No. 15/905,396, filed Feb. 26, 2018, now U.S. Pat. No. 10,238,600, whichis a continuation-in-part of U.S. application Ser. No. 15/866,729, filedJan. 10, 2018, now U.S. Pat. No. 10,195,142, which is a continuationapplication of U.S. application Ser. No. 15/486,331, filed Apr. 13,2017, now U.S. Pat. No. 9,901,545, the contents of each of which areincorporated herein by reference.

BACKGROUND OF THE INVENTION

Active ingredients, such as but not limited to drugs or pharmaceuticals,may be prepared in a tablet form to allow for accurate and consistentdosing. However, this form of preparing and dispensing medications hasmany disadvantages including a large proportion of adjuvants that mustbe added to obtain a size able to be handled, that a larger medicationform requires additional storage space, and that dispensing includescounting the tablets which has a tendency for inaccuracy. In addition,many persons, estimated to be as much as 28% of the population, havedifficulty swallowing tablets.

While tablets may be broken into smaller pieces or even crushed as ameans of overcoming swallowing difficulties, this is not a suitablesolution for many tablet or pill forms. For example, crushing ordestroying the tablet or pill form to facilitate ingestion, alone or inadmixture with food, may also destroy the controlled release properties,taste masking properties, or otherwise effect the pharmacokineticproperties of the drug.

As an alternative to tablets and pills, films may be used to carryactive ingredients such as drugs, pharmaceuticals, dermals,cosmeceuticals, botanicals and the like.

However, historically films and the process of making drug deliverysystems therefrom have suffered from a number of unfavorablecharacteristics, and the industry struggled to develop a commerciallyviable way to manufacture films for consumers.

Films that incorporate a pharmaceutically active ingredient aredisclosed in expired U.S. Pat. No. 4,136,145 to Fuchs, et al. (“Fuchs”).These films may be formed into a sheet, dried and then cut intoindividual doses. The Fuchs disclosure alleges the fabrication of auniform film, which includes the combination of water-soluble polymers,surfactants, flavors, sweeteners, plasticizers and drugs. Theseallegedly flexible films are disclosed as being useful for oral, topicalor enteral use. Examples of specific uses disclosed by Fuchs includeapplication of the films to mucosal membrane areas of the body,including the mouth, rectal, vaginal, nasal and otic areas.

Commentators have suggested that examination of films made in accordancewith the process disclosed in Fuchs, however, reveals that such filmssuffer from the aggregation or conglomeration of particles, i.e.,self-aggregation, making them inherently non-uniform. See U.S. Pat. No.8,658,437 (Yang et al., including the instant applicants) discussingFuchs. The formation of agglomerates randomly distributes the filmcomponents and any active present as well. When large dosages areinvolved, a small change in the dimensions of the film would lead to alarge difference in the amount of active per film. If such films were toinclude low dosages of active, it is possible that portions of the filmmay be substantially devoid of any active.

What constitutes true uniformity in a cast film? It is usually not atrue molecular uniformity but rather a dispersion of active in which agiven size film falls within generally accepted guidelines.

Since sheets of film are usually cut into unit doses, certain doses maytherefore be devoid of or contain an insufficient amount of active forthe recommended treatment. Failure to achieve a high degree of accuracywith respect to the amount of active ingredient in the cut film can beharmful to the patient. For this reason, dosage forms formed byprocesses such as Fuchs, would not likely meet the stringent standardsof governmental or regulatory agencies, such as the U.S. Federal DrugAdministration (“FDA”), relating to the variation of active in dosageforms.

Currently, as required by various world regulatory authorities, dosageforms may not vary more than 10% in the amount of active present. Whenapplied to dosage units based on films, this virtually mandates thatuniformity of the drug in the film be present.

The problems of self-aggregation leading to non-uniformity of a filmwere addressed in U.S. Pat. No. 4,849,246 to Schmidt (“Schmidt”).Schmidt specifically pointed out that the methods disclosed by Fuchs didnot provide a uniform film and recognized that that the creation of anon-uniform film necessarily prevents accurate dosing, which asdiscussed above is especially important in the pharmaceutical area.

Schmidt abandoned the idea that a mono-layer film, such as described byFuchs, may provide an accurate dosage form and instead attempted tosolve this problem by forming a multi-layered film. Schmidt forms aninitial water soluble wet cast film. Next, “an aqueous coating materialis prepared from the active ingredient, as well as starches, gelatins,glycerol and/or sorbitol, as well as optionally natural and/or syntheticresins and/or gums, and . . . the coating material is continuouslyapplied by means of a roll coating process and in a preciselypredetermined quantity (i.e via coating thickness) to at least one sideof the support film . . . . With the aid of modern roll applicationprocesses the active ingredient-containing coating can be applied with aconstant thickness, so that the necessary tolerances can be respected.”

The Schmidt process is a multi-step process that adds expense andcomplexity and is not practical for commercial use and is in fact nomore a guarantee of uniformity than is Fuchs. In fact, the Schmidtpatent has expired without, to the personal knowledge of the instantinventors, any commercial use. Yang et al describe a related approach,wherein, in a cast film, “particles or particulates may be added to thefilm-forming composition or matrix after the composition or matrix iscast into a film. For example, particles may be added to the film 42prior to the drying of the film 42. Particles may be controllablymetered to the film and disposed onto the film through a suitabletechnique, such as through the use of a doctor blade (not shown) whichis a device which marginally or softly touches the surface of the filmand controllably disposes the particles onto the film surface” (U.S.Pat. No. 9,108,340).

Other U.S. patents directly addressed the problems of particleself-aggregation and non-uniformity inherent in conventional filmforming techniques.

U.S. Pat. No. 5,629,003 to Horstmann et al. and U.S. Pat. No. 5,948,430to Zerbe et al. incorporated additional ingredients, i.e. gel formersand polyhydric alcohols in wet cast films, respectively, to increase theviscosity of the film prior to drying.

In addition to the concerns associated with degradation of an activeduring extended exposure to moisture, the conventional drying methodsthemselves may be unable to provide uniform films.

The length of heat exposure during conventional processing, oftenreferred to as the “heat history”, and the manner in which such heat isapplied, have a direct effect on the formation and morphology of theresultant film product.

Uniformity is particularly difficult to achieve via conventional dryingmethods where a relatively thicker film, which is well-suited for theincorporation of a drug active, is desired. Thicker uniform films aremore difficult to achieve because the surfaces of the film and the innerportions of the film do not experience the same external conditionssimultaneously during drying.

Thus according to commentators (U.S. Pat. No. 7,425,292), observation ofrelatively thick films made from such conventional processing shows anon-uniform structure caused by convection and intermolecular forces andmay require moisture to remain flexible. The amount of free moisture canoften interfere over time with the drug leading to potency issues andtherefore inconsistency in the final product.

Put simply, the practitioner may walk a tightrope between moistureneeded for desired mechanical attributes (flexibility of theself-supported film), and potentially deleterious consequences forchemical stability of the active ingredient associated with moisture.

Some discussion of mechanical attributes is important. In a conventionalwet cast film, the film is coated on a substrate, dried, then rolledonto itself. The film is then processed, i.e. cut. Typically the edgesare removed (trimmed), and the web (width) is cut into sub-widthsections that can be accommodated by the film packaging machine(typically called “conversion” of the film). The film may or may nothave been removed from its coating substrate, but either way requiressufficient mechanical strength to accommodate this processing.

If films lack the requisite pliability and tensile strength, they willtend to break during packaging causing substantial losses in processyield. Such breakage issues presumably led to the filing of a patent onmethods of film splicing by Novartis (Slominski et al US 20060207721A1). Some pliable, strong wet cast films, use polyethylene oxide (PEO)based compositions (See Yang et al. US 2005/0037055 A1). The strength ofthese films has led to the subsequent use of PEO in formulationscommercially sold by Novartis. The reality is that physical strength andresulting breakage and process yield issues caused by breakage have beensignificant problems for many of the non-PEO wet cast films.

However, as regards pliability again the practitioner walks a tightrope.If the film is too pliable, it may stretch (elongate), particularly inthe packaging stage where the film is under tension in the packaginglanes. Typically, in film packaging, the sub-roll of film is slit intolanes (each lane representing the width of the final dose) and thenprocessed into unit dose foil packages. The final dosage is premised onrelatively uniform distribution of drug in the film, and then cuttingequally dimensioned pieces of films based on the calculated drugconcentration. Hopefully that concentration is known ex ante (beforecoating), but it can also be determined ex post (after coating).

However, if the film is too pliable, it may stretch under tension (mostcommonly in the packaging stage here). The effect of such stretchingwill decrease the concentration of the drug in the film. For a“stretched” film, the given calculated dimensions (that did notanticipate stretch/elongation) will now yield an under-strength dosageform.

As a result, the formulator must provide a film that, when dried, issufficiently pliable to accommodate conversion. At the same time, thefilm cannot be too pliable or it will stretch.

Even if the film's mechanical properties are sufficient for conversionand packaging, physical stability of the final dosage form over time isnot necessarily assured.

The issue of physical stability is also an issue for wet castfilms--expensive barrier packaging is often used as a matter ofnecessity. Still, physical stability is not always a given. BootsChemists launched a Vitamin C strip manufactured by BioProgress in TampaFla. that had to be removed from the shelves because it was crumbling inthe package−earning the name “chips not strips.”

This story is not unique—many projects have failed to move out fromdevelopment to commercialization due to physical stability issues.

The formulator must accommodate these needs while still achieving therequired performance when used (e.g. desired disintegration time,desired muco adhesion if a buccal film etc).

Conventional drying methods generally include the use of forced hot airusing a drying oven, drying tunnel, and the like. The difficulty inachieving a uniform film is directly related to the rheologicalproperties and the process of water evaporation in the film-formingcomposition as well as but not limited to the matters described above.

When the surface of an aqueous polymer solution is contacted with a hightemperature air current, such as a film-forming composition passingthrough a hot air oven, the surface water is immediately evaporated andtheoretically forming a polymer film or skin on the surface. This canseal the remainder of the aqueous film-forming composition beneath thesurface, forming a barrier through which the remaining water must forceitself as it is evaporated in order to achieve a dried film. As thetemperature outside the film continues to increase, water vapor pressurebuilds up under the surface of the film, stretching the surface of thefilm, and ultimately ripping the film surface open allowing the watervapor to escape. As soon as the water vapor has escaped, the polymerfilm surface reforms, and this process is repeated, until the film iscompletely dried. The result of the repeated destruction and reformationof the film surface is observed as a “ripple effect” which produces anuneven, and often non-uniform film. Frequently, depending on thepolymer, a surface will seal so tightly that the remaining water isdifficult to remove, leading to very long drying times, highertemperatures, and higher energy costs.

Other factors, such as mixing techniques, also play a role in themanufacture of a pharmaceutical film, particularly a wet cast film,suitable for commercialization and regulatory approval. Air can betrapped in the composition during the mixing process or later during thefilm making process, which can leave voids in the film product as themoisture evaporates during the drying stage. The film may collapsearound the voids resulting in an uneven film surface and therefore,non-uniformity of the final film product. Uniformity is still affectedeven if the voids in the film caused by air bubbles do not collapse.This situation also provides a non-uniform film in that the spaces,which are not uniformly distributed, are occupying area that wouldotherwise be occupied by the film composition and more importantlybecause there is a single mix in prior art casting, voids mean “noactive present” here.

Some discussion of coating methods is needed, and the present inventorsprovide a good primer in U.S. Pat. No. 7,824,588 (Yang et al includingthe present inventors):

“Coating or casting methods are particularly useful for the purpose offorming the films of the present invention. Specific examples includereverse roll coating, gravure coating, immersion or dip coating,metering rod or meyer bar coating, slot die or extrusion coating, gap orknife over roll coating, air knife coating; curtain coating, orcombinations thereof, especially when a multi-layered film is desired.In this procedure, the coating material is measured onto the applicatorroller by the precision setting of the gap between the upper meteringroller and the application roller below it. The coating is transferredfrom the application roller to the substrate as it passes around thesupport roller adjacent to the application roller. Both three roll andfour roll processes are common.”

“The gravure coating process relies on an engraved roller running in acoating bath, which fills the engraved dots or lines of the roller withthe coating material. The excess coating on the roller is wiped off by adoctor blade and the coating is then deposited onto the substrate as itpasses between the engraved roller and a pressure roller.”

“Offset Gravure is common, where the coating is deposited on anintermediate roller before transfer to the substrate.”

“In the simple process of immersion or dip coating, the substrate isdipped into a bath of the coating, which is normally of a low viscosityto enable the coating to run back into the bath as the substrateemerges.”

“In the metering rod coating process, an excess of the coating isdeposited onto the substrate as it passes over the bath roller. Thewire-wound metering rod, sometimes known as a Meyer Bar, allows thedesired quantity of the coating to remain on the substrate. The quantityis determined by the diameter of the wire used on the rod.”

“In the slot die process, the coating is squeezed out by gravity orunder pressure through a slot and onto the substrate. If the coating is100% solids, the process is termed ‘Extrusion.”’

The '588 continues: “The gap or knife over roll process relies on acoating being applied to the substrate which then passes through a ‘gap’between a ‘knife’ and a support roller. As the coating and substratepass through, the excess is scraped off. Air knife coating is where thecoating is applied to the substrate and the excess is ‘blown off’ by apowerful jet from the air knife. This procedure is useful for aqueouscoatings. In the curtain coating process, a bath with a slot in the baseallows a continuous curtain of the coating to fall into the gap betweentwo conveyors. The object to be coated is passed along the conveyor at acontrolled speed and so receives the coating on its upper face.”

Yang et al, including the present inventors, teach a “selection of apolymer or combination of polymers that will provide a desiredviscosity, a film-forming process such as reverse roll coating, and acontrolled, and desirably rapid, drying process which serves to maintainthe uniform distribution of non-self-aggregated components without thenecessary addition of gel formers or polyhydric alcohols.” See U.S. Pat.No. 9,108,340.

Yang et al. strongly rely on viscosity in the pre-cast film solution tomaintain drug content uniformity, and on said viscoelastic properties ofthe film composition to retard and avoid excess migration of drug duringboth the casting and drying process.

As U.S. Pat. No. 8,603,514 (Yang et al.) describes: “the viscosity ofthe liquid phase is critical and is desirably modified by customizingthe liquid composition to a viscoelastic non-Newtonian fluid with lowyield stress values. This is the equivalent of producing a highviscosity continuous phase at rest. Formation of a viscoelastic or ahighly structured fluid phase provides additional resistive forces toparticle sedimentation. Further, flocculation or aggregation can becontrolled minimizing particle-particle interactions. The net effectwould be the preservation of a homogeneous dispersed phase.”

Yang et al. invoke Stokes' law to support this high viscosity approach.U.S. Pat. No. 8,603,514 describes: “One approach provided by the presentinvention is to balance the density of the particulate (ρ_(p)) and theliquid phase (ρ₁) and increase the viscosity of the liquid phase(μ). Foran isolated particle, Stokes law relates the terminal settling velocity(Vo) of a rigid spherical body of radius (r) in a viscous fluid, asfollows: V_(o)=(2gr^(r))(ρ_(p)−ρ₁)/9 μ”

Accordingly, claim 1 of U.S. Pat. No. 8,603, 514 requires, inter alia,the following element concerning the viscosity of the film formingmatrix: “matrix has a viscosity sufficient to aid in substantiallymaintaining non-self-aggregating uniformity of the active in thematrix.”

The film compositions of Yang et al. (and other film artisans citedabove) are so viscous that mechanical means (i.e. a physicalmeans/physical object) in contact with the composition) are required toform a film by spreading the film composition on to the substrate. Putsimply, the compositions are too viscous and have surface tension thatis too high to pour. This is helpful in the coating process; after all,if the composition were too flowable it would roll/flow off thesubstrate. US 8,906,277 (Yang et al.) describes the ability of themechanical coating apparatus as providing the upper limit on viscosityof the film formulation: “the viscosity must not be too great as tohinder or prevent the chosen method of casting, which desirably includesreverse roll coating due to its ability to provide a film ofsubstantially consistent thickness.”

After the Yang et al. film compositions have been coated, Yang et al.describe a controlled drying process to avoid agglomeration of drug andresultant loss of content uniformity.

U.S. Pat. No. 8,603,514 (Yang et al.) describes: “In conventional ovendrying methods, as the moisture trapped inside subsequently evaporates,the top surface is altered by being ripped open and then reformed. Thesecomplications are avoided by the present invention, and a uniform filmis provided by drying the bottom surface of the film first or otherwisepreventing the formation of polymer film formation (skin) on the topsurface of the film prior to drying the depth of the film. This may beachieved by applying heat to the bottom surface of the film withsubstantially no top air flow, or alternatively by the introduction ofcontrolled microwaves to evaporate the water or other polar solventwithin the film, again with substantially no top air flow. Yetalternatively, drying may be achieved by using balanced fluid flow, suchas balanced air flow, where the bottom and top air flows are controlledto provide a uniform film. In such a case, the air flow directed at thetop of the film should not create a condition which would cause movementof particles present in the wet film, due to forces generated by the aircurrents. Additionally, air currents directed at the bottom of the filmshould desirably be controlled such that the film does not lift up dueto forces from the air. Uncontrolled air currents, either above or belowthe film, can create non-uniformity in the final film products. Thehumidity level of the area surrounding the top surface may also beappropriately adjusted to prevent premature closure or skinning of thepolymer surface.”

“This manner of drying the films provides several advantages. Amongthese are the faster drying times and a more uniform surface of thefilm, as well as uniform distribution of components for any given areain the film. In addition, the faster drying time allows viscosity toquickly build within the film, further encouraging a uniformdistribution of components and decrease in aggregation of components inthe final film product.”

High viscosity, high surface tension, and difficult flowability is agiven in coating line systems. The picture at this link shows(www.matik.com/olbrich-answers-the-call-from-customers/) a standardOlbrich coating line. Olbrich is a leading manufacturer of coatingequipment. The coating apparatus is physically below the drying tunnel,with the freshly coated substrate taking off at a severe (high) anglegoing up to the drying tunnel. When before any drying, it is necessarythat the freshly coated film will not roll or flow off the substratedespite gravitational forces associated with this take off angle. It isimportant to note that drying methodology here is essential touniformity. In the invention to be described here, the dose unit isconfined and the drying method has substantially no role in dosageuniformity.

The Yang et al. approach has proved dominant in the marketplace forfilm. The most successful commercial orally soluble film product(measured by sales) is Suboxone® thin film, which has exceeded onebillion in US sales in certain years. The FDA Orange Book references twopatents of Yang and the present inventors in connection with Suboxone:U.S. Pat. No. 8,017,150 and U.S. Pat. No. 8,603,514. A third patentlisted in the Orange Book for this product—U.S. Pat. No. 8,475,832 whichdeals with pH issues specific to Suboxone (as distinct from wet castfilm manufacture generally)—has been found invalid by the District Courtfor Delaware (although this '832 pH patent may be under further judicialappeal).

To date, several sophisticated ANDA filers, including WatsonPharmaceuticals, TEVA Pharmaceuticals (the world's largest genericcompany with revenues exceeding twenty billion dollars) and PARPharmaceuticals, have been unable in judicial proceedings to shownon-infringement (or invalidity) of the Suboxone-Orange Book listedpatents. Watson and Par and have been forbidden from launching genericfilm products, and a decision in the TEVA cases is expected shortly.

The next largest commercial orally soluble film success is theacquisition by Sunovion of Cynapsus for $624 million USD to acquireCynapsus' apomorphine sublingual film. Cynapsus has a licensingarrangement to the same patent estate as Suboxone according to publiclyavailable information(/2016/04/04/825387/0/en/Cynapsus-Therapeutics-and-MonoSol-Rx-Announce-Global-IP-Licensing-Agreement.html).Moreover, the owner of the same patent estate recently sued BioDeliverySciences for patent infringement for its Belbuca™ product, claiminginfringement of another progeny of the same patent estate, U.S. Pat. No.8,765,167 (Yang et al).

The applicants are not aware of any orally soluble film product withsignificant sales that does not license this patent estate.

The subject of loss (yield) and wet casting must be addressed. As wehave discussed, wet cast film compositions are very viscous in theinitial mixing stage. This viscosity, together with high surfacetension, means that the film composition will experience loss withadhered product in the mixing apparatus and tubing from the mixingapparatus to the coater. Some mild loss may occur on the coatingapparatus itself. There will be initial loss of product to bring thecoater online until the product is running at standard parameters.Similarly, there will be loss at the end of a run bringing the coateroff line (i.e. when too little material remains to maintain the coaterrunning at standard parameters). As discussed, supra, product will belost in the conversion stage by edge trimming, as well as cases wherethe width of usable web does not evenly divide by the input widthrequired by the packaging line.

The packaging machine must be brought online (and offline at the end ofa run), necessitating waste. Any breakage of film during packaging willresult in waste in connection with lost product and restarting of theline. And so on—this is not a non-limitative list, but offers someinsight into the innate wastefulness of the process

The fact is that yields of wet cast film products are low, can result insubstantial product loss, which is particularly concerning when castingexpensive active pharmaceutical ingredients (API) (excipients beingrelative inexpensive by comparison to API). Loss can be higher than 25%of API, high as 35% API and even approaching 50% API loss. Such API lossmay be acceptable for high value branded targets, but ultimatelyrestricts the success of oral soluble film in competitive Rx, OTC andother consumer fields.

The oral soluble film format is generally preferred by consumers overorally disintegrating tablets, but the latter is currently lessexpensive to make (as compared with wet cast films). For example,generic ondansetron orally disintegrating tablets sell for $8/dose (www.drugs. com/price-guide/ondansetron#oral-tablet-disintegrating-4-mg);whereas ondansetron orally soluble film has a retail price of $35/dose(www.drugs.com/price-guide/zuplenz). In an era when drug prices areunder fire publicly, and third party payers take a hard pencil toformulary reimbursement rates, this is a hard price differential tosupport. For orally soluble film to help deliver value to more patients,a more cost effective method of film manufacture is needed.

One way to avoid some of the product loss associated with wet casting ishot melt extrusion. Insofar as an extruder acts as a mixer and typicallystarts with substantially dry, non-aqueous compositions, hot meltextrusion avoids mixing loss associated with wet casting.

One of the present applicants has two US patents dealing with hot meltextrusion products and methods: U.S. Pat. No. 9,125,434 (Fuisz) and U.S.Pat. No. 8,613,285 (Fuisz). Hot melt extrusion offers other advantagesincluding a much smaller manufacturing footprint than a wet castingline, and the ability to make longer lasting films/sheets than can bemade with wet casting. However, hot melt extrusion as a process has itsown limitations (vis a vis wet casting). A principal limitation of hotmelt extrusion is a smaller menu of film formers that readily extrude,which makes formulation far more challenging (as compared with wetcasting). Taste masking and controlled release may also be harder.Despite its strengths, applicants are not aware of any significantcommercial film product made using hot melt extrusion, and applicantsbelieve that the smaller menu of available film formers is a reason forthis.

Discussion of the Zydis system is appropriate. The Zydis system is anorally disintegrating tablet, and is classified by the FDA as such (asdistinct from orally soluble film). The Zydis system is well regardedfor its rapid disintegration (relative to other orally disintegratingtablets), though the system has some limitations in terms of drugloading and taste masking. A primer on the history of orallydisintegrating tablets, including reference to one of the presentinventors, is available here:en.wikipedia.org/wiki/Orally_disintegrating_tablet.

The Zydis system, which is a freeze-dried tablet, is described in U.S.Pat. Nos. 4,371,516; 4,305,502; 4,758,598; 4,754,597, and 5,631,023, theteachings of all of which are incorporated herein by reference as iffully herein stated. The Zydis manufacturing method uses a pre-preparedliquid composition including a solvent, a granular therapeutic agent,and a gelatin containing carrier material.

The liquid composition (including the drug) is placed into one or moreshaped depressions in a tray or mold to define liquid composition filleddepressions. The liquid composition in the filled depressions is frozen,then the liquid portion of the liquid composition sublimed to define asolid medicament tablet. Sublimation is accomplished by freeze dryingand can take several days. Thus, the tablet manufacturing process is notcontinuous; Zydis tablets-in-sublimation are stored in racks in aspecial chamber for sublimation. Only after sublimation can they bepackaged.

Some mention of the CIMA orally disintegrating tablet is appropriate.The CIMA tablet uses a base-acid reaction (effervescence) to effect oraltablet disintegration. There is some support for the proposition thateffervescence enhances buccal absorption. See U.S. Pat. No. 6,200,604which is hereby incorporated by reference. Applicants are aware of nocommercial oral soluble film product with effervescence, and attributethis to the practical difficulties of including acid and base in a wetcast film composition (without the product prematurely effervescing).

Finally, some mention of three dimensional printing is warranted. 3Dprinting has garnered much attention as a possible method formanufacturing pharmaceutical dosage forms. The products are printedlayer by layer (using binding materials in between the layers of powderto adhere powder one layer to the other). The reality has failed to meetthe hype, although a single printed dose product approval was obtainedby Aprecia Pharmaceuticals for a product using its Zipdose technologylicensed from MIT.

Applicants hereby incorporate by reference their oral film prior patentsas if fully stated herein — these include: U.S. Pat. No. 7,425,292 (Thinfilm with non-self-aggregating uniform heterogeneity and drug deliverysystems made therefrom); U.S. Pat. No.7,666,337 (Polyethyleneoxide-based films and drug delivery systems made therefrom); U.S. Pat.No.7,824,588 (Method of making self-supporting therapeuticactive-containing film); U.S. Pat. No.7,897,080 (Polyethylene-oxidebased films and drug delivery systems made therefrom); U.S. Pat.No.7,972,618 (Edible water-soluble film containing a foam reducingflavoring agent); U.S. Pat. No.8,017,150 (Polyethylene oxide-based filmsand drug delivery systems made therefrom); U.S. Pat. No.8,568,777(Packaged film dosage unit containing a complexate); U.S. Pat.No.8,603,514 (Uniform films for rapid dissolve dosage form incorporatingtaste-masking compositions); U.S. Pat. No. 8,613,285 (Extrudable andextruded compositions for delivery of bioactive agents, method of makingsame and method of using same); U.S. Pat. No. 8,617,589 (Biocompatiblefilm with variable cross-sectional properties); U.S. Pat. No. 8,652,378(Uniform films for rapid dissolve dosage form incorporatingtaste-masking compositions); U.S. Pat. No.8,663,687 (Film compositionsfor delivery of actives); U.S. Pat. No. 8,685,437 (Thin film withnon-self-aggregating uniform heterogeneity and drug delivery systemsmade therefrom); U.S. Pat. No.8,900,498 (Process for manufacturing aresulting multi-layer pharmaceutical film); U.S. Pat. No.8,906,277(Process for manufacturing a resulting pharmaceutical film); U.S. Pat.No.9,108,340 (Process for manufacturing a resulting multi-layerpharmaceutical film); U.S. Pat. No. 9,125,434 (Smokeless tobaccoproduct, smokeless tobacco product in the form of a sheet, extrudabletobacco composition); and U.S. Pat. No.9,150,341 (Unit assembly andmethod of making same).

SUMMARY OF THE INVENTION

One aspect of the invention relates to an oral soluble film containingat least one active agent, the oral soluble film being made by a methodcomprising providing a well of a predetermined size; depositing a filmforming composition in the well; metering a predetermined amount of anactive agent composition in the well separately from the film formingcomposition, the active agent composition being different than the filmforming composition, the film forming composition and the active agentcomposition forming a single layer in the well; and drying the singlelayer in the well to form the oral soluble film containing the at leastone active agent.

Another aspect of the invention realates to an oral soluble filmcontaining at least one active agent, the oral soluble film being madeby a method comprising continuously stirring a suspension of a filmforming composition and particulates of at least one active agent in atank; depositing the suspension of the film forming composition and theparticulates of the at least one active agent separately into each of aplurality of wells while continuously stirring the suspension in thetank, the suspension of the film forming composition and theparticulates of the at least one active agent having a yield stress ofless than 30 Pa and forming a contact angle with the well of less than90.degree., wherein the suspension of the film forming composition andthe particulates of the at least one active agent flows into a film inthe well within 20 seconds and has a viscosity below 600 centipoise; anddrying the film using hot air currents to form the oral soluble filmcontaining the at least one active agent.

In another aspect, the invention relates to a multi-layered filmcomprising a plurality of layers, at least one of the plurality oflayers being an oral soluble film layer containing at least one activeagent, the at least one oral soluble film layer being made by a methodcomprising providing a well of a predetermined size; depositing a filmforming composition in the well; metering a predetermined amount of anactive agent composition in the well separately from the film formingcomposition, the active agent composition being different than the filmforming composition, the film forming composition and the active agentcomposition forming a single layer in the well; and drying the singlelayer in the well to form the at least one oral soluble film layercontaining the at least one active agent. The multi-layered may includean insoluble backing layer. The multi-layered film may include asemi-insoluble backing layer. The multi-layered film may have multiplelayers each with a different active agent.

In another aspect, the invention relates to a multi-layered filmcomprising a plurality of layers, at least one at least one of theplurality of layers being an oral soluble film layer containing at leastone active agent, the oral soluble film layer being made by a methodcomprising continuously stirring a suspension of a film formingcomposition and particulates of at least one active agent in a tank;depositing the suspension of the film forming composition and theparticulates of the at least one active agent separately into each of aplurality of wells while continuously stirring the suspension in thetank, the suspension of the film forming composition and theparticulates of the at least one active agent having a yield stress ofless than 30 Pa and forming a contact angle with the well of less than90.degree., wherein the suspension of the film forming composition andthe particulates of the at least one active agent flows into a filmlayer in the well within 20 seconds and has a viscosity below 600centipoise; and drying the film using hot air currents to form the oralsoluble film layer containing the at least one active agent. Themulti-layered may include an insoluble backing layer. The multi-layeredfilm may include a semi-insoluble backing layer. The multi-layered filmmay have multiple layers each with a different active agent.

Another aspect of the present invention relates to a method of making anoral soluble film, containing at least one active agent. The methodincludes providing a well of a predetermined size; depositing a filmforming composition in the well; depositing an active agent compositionin the well, the active agent composition being different than the filmforming composition, the film forming composition and the active agentcomposition forming an admixture in the well; and drying the admixturein the well.

Depositing of the film forming composition in the well and depositing ofthe active agent composition in the well can be carried out sequentiallyor simultaneously from two separate depositiong devices. If sequentialdeposition is used, the active agent composition is preferably but notnecessarily deposited in the well first and then the film formingcomposition is deposited in the well.

In another aspect of the invention, a method of making an oral solublefilm, containing at least one active agent, includes providing a well ofa predetermined size; depositing a film forming composition including atleast one active agent in the well, the film forming composition havinga viscosity below 2000 centipoise; and drying the film formingcomposition in the well.

In still another aspect of the invention, a film forming composition,suitable for making an oral soluble film, has sufficiently low viscosityand surface tension to flow into a film without mechanical interventionwhen deposited in a well.

Another aspect of the invention relates to a package, system and methodsfor custody and control of drugs, especially for an abuse-prone drug.

One aspect includes a package for custody and control of a dose of anactive agent, including a unit dose of an active agent, and anindividual package sealing the unit dose therein, the package having acustody and control product identifier unique to each unit dose providedon the package. This Custody and Control (C&C) is separate and distinctfrom a lot identifier, and the C&C also differs in being unique to eachpackaged dosage unit. In some embodiments, the unit dose may beconfigured to substantially lose its potency when removed from thepackage.

Another aspect is a system for custody and control of a dose of anactive agent, including an individual package of one unit dose of anactive agent, the package having a custody and control productidentifier unique to each unit dose provided on the package, and adatabase containing data reflecting the custody and control identifiercorresponding to each unit dose and an identifier configured to be ableto identify the party to whom each unit dose is provided.

In still another aspect, a method for custody and control for anabuse-prone drug, includes providing an individual package of one unitdose of an active agent, the package having a custody and controlproduct identifier unique to each unit dose provided on the package, andrecording data reflecting the custody and control identifiercorresponding to each unit dose and an identifier configured to be ableto identify the party to whom each unit dose is provided.

In still another aspect, a method for custody and control for anabuse-prone drug, includes obtaining an individual package of one unitdose of an active agent, the package having a custody and controlproduct identifier unique to each unit dose provided on the package, andrecording data reflecting the custody and control identifiercorresponding to each unit dose and an identifier configured to be ableto identify the party to whom each unit dose is provided. This C&Cidentifier may also be placed in the bottom the C&C package as well.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a roll of pre-formed molds or wellsprior to filling.

FIG. 2 is a perspective view showing a deposit device filling a well ofthe roll of pre-formed molds or wells.

FIG. 3 is an enlarged view of a portion in FIG. 2 showing a depositdevice filling a well with a film former composition.

FIG. 4 is an enlarged view of a portion in FIG. 2 showing a depositdevice filling a well with active pharmaceutical ingredient withoptional excipients, in particulate form.

FIG. 5 is a perspective view showing a drying device deploying hot aircurrents from above the roll of film wells (which have been alreadyfilled).

FIG. 6 is a perspective view showing adhesive being applied to welledges of bottom sheet.

FIG. 7 is a perspective view showing a roll of wells, with films (anddrug) deposited, films formed and dried, and guideposts inserted in theends of the roll of wells for alignment of the top sheet which is placedover the bottom sheet.

FIG. 8 is a perspective view showing a roll of wells, with films (anddrug) deposited, films formed and dried, guideposts, and serration ofindividual doses within the roll of wells.

FIG. 9 is a perspective view showing a finished dosage form removed froma roll of wells, the breakage lines occurring at the lines of serration.

FIGS. 10-14 show rheological properties of some of the Examples.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention relates to a system formanufacturing an oral soluble film with an active agent, e.g., apharmaceutical oral soluble film by the deposition of active and filmformer composition separately into a mold or well.

One aspect of the present invention relates to a system formanufacturing an oral soluble film with an active agent, e.g., apharmaceutical oral soluble film by the deposition of activepharmaceutical agent(s) and film former together into a mold or well.

One aspect of the present invention relates to a system of continuousmanufacture (formation of oral soluble films) and primary packaging ofthe oral soluble films.

One aspect of the present invention relates to a system formanufacturing an oral soluble film in which the active agent isdeposited into a mold or well separately from the film former, and thedrug binds or diffuses adequately mixes into the final, dried filmmatrix.

One aspect of present invention relates to a method of forming an oralsoluble film with an active agent, e.g., a pharmaceutical oral solublefilm without direct mechanical intervention to spread and/or coat and/orcast the composition into a film, such as by deposit of a sufficientlyflowable film former composition into a well or mold and.

One aspect of the present invention relates to the use of a compressedgas to encourage and/or speed the flow of a film composition into a filmshape in a mold or well.

One aspect of the present invention relates to the use of a compressedgas to encourage mixing of an active agent with a film formercomposition in a mold or well.

One aspect of the present invention relates to the use of briefvibration to encourage and/or speed up mixing of an active agent with afilm former composition in a mold or well.

One aspect of the present invention relates to the use of briefvibration to encourage and/or speed up the flow of a film compositioninto a film well shape.

One aspect of the present invention relates to the manufacture of afilm-sheet 1 to 40 mils (measured as dry thickness). This is nonlimiting and the methodology here allows for thick films and for dermalproducts.

One aspect of the present invention relates to a mold or well shape thatis optimized for film formation by deposit method.

One aspect of the present invention replaces to mold or well materialthat is selected to be a suitable surface energy substrate to facilitatewetting and spreading of film former composition, i.e. low contact angleand/or surface tension.

One aspect of the present invention relates to pre-treating a mold orwell with a surface active agent, a surfactant, or other agent to eitherpromote flow of the film composition, and/or promote easier release ofthe dried film.

One aspect of the present invention relates to a composition suitablefor making an oral soluble film where the viscosity and/or surfacetension and/or interfacial tension of the composition (with thewell/mold material, as applicable) is selected to promote flowability ofsaid composition sufficient to form a film in a mold or well, and incertain embodiments to form such a film rapidly in such mold or well.This categorically teaches away from cast film art in that highviscosity is antithetical to successful formation of a deposit byprecluding adequate flowability of the film former composition into amold or well.

One aspect of the present invention relates to a film former compositionwith sufficient wettability to mix adequately in a mold or well with aseparately deposited active.

One aspect of the present invention relates an oral soluble film madewith one or more low molecular weight polymers as film formers

One aspect of the present invention relates to a composition suitablefor making an oral soluble film by the deposit method, where suchcomposition is not capable of being wet cast into a film usingtraditional wet cast coating technologies (e.g. by three roll coater, ordoctor blade).

One aspect of the present invention involves an alignment system toensure the mold or well sheet is aligned with the top sheet. Forexample, aligning openings on the well sheet and the top sheet may beused so that through, for example, a pin type alignment each is properlyoriented to the other.

One aspect of the present invention relates to a drying process that issuitable for the deposited composition to immediately flow into theshape of the mold or well prior to becoming too viscous to flow as aresult of loss of solvent effecting viscosity increase.

One aspect of the present invention relates to the material of the moldor well selected that is suitable for the flow of the composition into afilm.

One aspect of the present invention relates to the material of the moldor well selected to simultaneously allow the flow of the readily flowingcomposition while also allowing the dried material to be readily removedor peeled away from the well.

One aspect of the present invention relates to the design of the mold orwell so that a user can readily remove the film.

One aspect of the present invention can allow the dosage unit to besealed (primary packaging) on the same production line as the film ismanufactured if desired. Alternatively, the dosage unit can be sealed onan adjacent packaging line. Standard packaging at a later time is alsoallowable.

One aspect of the invention relates to the substrate/laminate layer withpre-formed wells made at line or before line by blister forming methods.

One aspect of the present invention relates to the blisters beingcollapsible such that when the substrate layer is rolled up on itself,the film within it is loosened enabling easy subsequent removal by theuser.

One aspect of the present invention relates to the manufacture andpackaging of an oral soluble film with minimal composition and API loss(less than 30% preferably less than 20%, most preferably less than 10%).

One aspect of the present invention relates to a oral soluble filmcomposition that has little or no yield stress. Such compositions areparticularly well suited for the present invention (i.e. formation of anoral soluble film by deposit method).

One aspect of the invention involves a rolled adhesive onto the driedbottom sheet/mold/well edges, but excluding the interior of thesheet/mold/wells, so that top sheet can be adhered.

One aspect of the present invention relates to a film former compositionwith a viscosity below 2000 centipoise, preferably below 1000, morepreferably below 600 centipoise, still more preferably below 300centipoise. Such measurements, in the case of a Non-Newtonian filmformer composition, are measured at low shear rate, <10 s⁻¹

One aspect of the present invention relates to the use of viscosityreducing agents in oral soluble film compositions. This teaches againstthe viscosity needed in traditional, wet cast films.

One aspect of the present invention relates to an oral soluble film withsufficiently uniform thickness and appearance for the user, withoptional uniform distribution of components in the film. One embodimentof the present invention relates to an oral soluble film that does nothave uniform distribution of active agent within the film.

One aspect of the present invention relates to an oral soluble film,made by deposit method, with <20% variability in height, preferably with<10% variability in height (measured from the thickest portion of thefilm to the thinnest portion, measured vertically).

One aspect of the present invention relates to an oral soluble film,made by deposit method, with one or more active agents, e.g., activepharmaceutical agents, wherein the content of said active pharmaceuticalagent(s) varies less than 10% from the label claim, preferably less than5%, preferably less than 2% from the label claim.

One aspect of the present invention relates to a multi-layer film madeby deposit method.

One aspect of the present invention relates to the manufacture of atransdermal film, in whole or in part, by the deposit method.

One aspect of the present invention relates to a dose with a uniqueidentifier on the dose itself and/or primary packaging.

One aspect of the present invention relates to the recordation of aunique dose identifier when dispensed or in connection with thedispensing of said dose to a given patient.

One aspect of the present invention relates to a dose which is hasintentionally compromised physical or chemical stability when removedfrom primary packaging, and or an inability to maintain its stabilityand individuality when removed from its containment.

One aspect of the present invention relates to a dose system comprisinga jelly, gelatin (e.g., of the type sold under the brand name Jell-O byKraft Foods), jam, mousse, pudding or similar base material. Somejellies and gelatins rely on gelatin made from animal collagen for theirunique textures. However, the present invention also can use jellies orgelatins using vegetarian substitutes for animal collagen.

One aspect of the present invention relates to a custody control systemto monitor the custody of abuse prone drugs.

One aspect of the present invention relates to a custody control systemthat reduces the diversion and or abuse of abuse prone drugs to astatistically significant degree.

One aspect of the present invention relates to a custody control systemthat reduces the street value of abuse prone drugs (in primary packagingand/or removed from primary packaging) to a statistically significantdegree.

In addition, this invention addresses the scourge in drug abuse with thecustody and control (C&C) of certain medications. The invention isuseful for C&C of any active ingredient but is especially useful forabuse-prone drugs, including but not limited to painkillers such asopiates, sleeping pills or sedatives, anti-anxiety medications, andstimulants.

One aspect of the present invention relates to a record made by thedispensing Pharmacist of an identifiable end user for purposes ofcustody and control. This is particularly beneficial with other aspectsof the current invention, insofar as traditional forms such as tabletsand capsules can too easily be removed from their custody and controlcontainers and kept loosely to avoid the identification of the originaluser. Thus films, which can be fragile, and gelatin and jellies andjams, all the aforementioned put in common with a custody and controlpouch or container, now become a new dosage form which allows bettercontrol of abuse prone drugs and their tracking of abused. The fragiledosage forms allow for the avoidance of ease of pre-separation of drugfrom custody and control containment, i.e., separation prior to use inthe manner and for the individual subscribed.

Avoidance of ease of pre-separation can be achieved in a variety ofdifferent ways, as discussed herein. One method is a dosage form withreduced physical and/or chemical stability when removed from theoriginal primary package. The dosage form may also simply be challengingto handle by would be outside of the original primary package, i.e. likea jelly, jam, gelatin, gel or liquid.

Certain embodiments of the custody and control system employ films madeby deposit, as taught in this specification. However, the custody andcontrol system may apply to other dosage forms that are made by deposit(e.g. gels, jellies, jams, gelatin, marshmallow, pudding, mouse, pannacotta, and liquids such as solutions, suspensions and emulsions).However, the custody and control invention is not limited to the depositmethods, and various embodiments of the custody and control system willuse dosage forms not made by deposit methodologies (e.g. conventionaltablets, orally disintegrating tablets, capsules, and other conventionaldosage forms which require containment for maintenance of potency)

In one aspect of the present invention, the unit dose, e.g., the topsheet thereof, is individually and preferably sequentially numbered orotherwise marked with a unique identification code so that the unit dosewell can be traced in abuse prone drugs, or other drugs for whichtraceability is desired. This makes the unit dose pack of the presentinvention more advantageous than other forms of individual doses such astablets that can not be individually numbered. A unit dose pack here canbe. Hence with the opioid and other abuse drug, by the dispensingpharmacist simple recording that dose number, e.g., 1724-1744, was givento John Jones, if the package is ever involved in contraband it can betraced to origin.

Of course, the numbering system may be used anywhere on primarypackaging (generally unit dose), secondary packaging, and indeed on thedosage form itself. RFID tag or similar technologies may be integrated,again at the level of the secondary packaging, primary packaging, or inthe dosage form itself. Generally, the numbering (or otheridentification) will be sequential. Numbering and the location ofnumbering is further discussed below.

The custody and control identifier is tied to the individual dose,optionally though each distributing intermediary, and ultimately theidentity of an individual patient; thus it is a distinct concept fromthe “lot number” that corresponds to manufacturing lots only.

Traditionally, the physical and chemical stability are traits that aredesired in film dosage forms, and more broadly in other dosage forms(i.e. tablets, capsules, suppositories, gels, liquids and othersincluding jelly, gelatin and jam discussed below). Indeed, physical andchemical stability are required traits to support basic shelf lifeclaims (commonly two years at the geographic appropriate ICHconditions).

Typically, orally dissolving formats like thin films and orallydissolving tablets use the barrier properties associated with their unitdosage packaging to reach acceptable stability (often foil or aclarpackaging with strong barrier properties). Outside of such packaging,such dosage forms which are frequently hydrophilic will see stabilityproblems outside of the packaging. Other dosage forms, too, includinggels require barrier packaging. Such stability issues however areconsidered a negative, and require expensive packaging, and somethingthat artisans attempt to avoid. Certain conventional dosage forms—liketablets and capsules—generally meet acceptable stability criteriawithout any packaging.

For the present invention, certain embodiments intentionally seek aproduct with increased stability problems (chemical and/or physical)when outside of the primary package, with a view to reducing the valueof the dosage form for abuse once it is removed from its originalpackaging.

By correlating instability to removal from the product's primarypackaging, it is intended to increase the importance and value ofpatient traceability of the dose and packaging for purposes of custodycontrol. This is particularly useful with opioids and other abusableactives, and teaches away from the typical imperative in productformulation and development to promote and extend product stability.

The degradation of drugs and drug metabolites in samples can occurthrough either reversible or irreversible processes. Common factors thataffect this stability include but are not limited to temperature, light,pH, oxidation and enzymatic degradation. Generally, however, forpurposes of the present invention the inventors can only rely onpredictable normal atmospheric conditions for the product. Moreover, theproduct should still be safe to consume, even when unstable or inactive.Preferably, the product is similarly still safe or relatively safe tomisuse or abuse, for example by injection or snorting of a drug nototherwise intended for such consumption.

There are five major types of drug stability (and instability) and theyare physical stability, chemical stability, microbiological stability,pharmacological stability, and toxicological stability. Generally,embodiments of the present invention will involve failure of physicalstability or chemical stability, but may also involve other forms ofstability (instability) as well.

it also may be an object of the present invention to have a dosage formthat is configured to substantially lose its potency. Known,conventional drugs and active agents are configured or engineered toretain their potency for as long as possible or at least through theexpiration date marked on the package for the drug or active agent. Oneaspect of the present invention can use a dosage form that is configuredto retain its potency through its expiration date while sealed in thepackage but is configured or engineered to lose its potency when removedfrom the primary package. For example, the dosage form may configured toretain its potency through its expiration date while sealed in thepackage but be configured or engineered to lose at least 20% of itspotency within six month(s), when removed from the package. Preferably,the dosage form loses greater than 20% potency, preferably greater than30% potency, and more preferably greater than 40% potency and mostpreferably greater than 80% potency. Such potency loss may occur withinone month, two months, three months, four months, five months or sixmonths. Such potency is measured by standard assay methods using ICHconditions for geographic zones 1 or 2. Potency loss may occur withinseconds, minutes, weeks or within three months after being removed fromthe original packaging and subject to ambient conditions. in someembodiments, potency loss may take up to six months to occur at ambientconditions.

In certain embodiments, the dosage form stability when removed from thepackage will be half as long as when in the package (i.e. to falloutside 90% potency) (i.e. one year instead of two years), preferably athird as long (i.e. 8 months instead of two years), more preferable atenth as long (i.e. 2.5 months instead of two years).

Hydrolysis may degrade drugs. Drugs with functional groups such asesters, amides, lactones or lactams may be susceptible to hydrolyticdegradation. It is probably the most commonly encountered mode of drugdegradation because of the prevalence of such groups in medicinal agentsand ubiquitous nature of water. Agents, like desiccants, may be used ineffective amounts in the dosage form to facilitate and encouragehydrolysis. Such agents may be particularly effective where the dosageform is otherwise comprised of excipients that are dissolvable orreadily dissolvable in aqueous media. Desiccants may include, withoutlimitation, silica based materials, activated charcoal, calcium sulfate,calcium chloride, and molecular sieves.

The use of desiccants in formulation favors dosage forms made from dryor substantially dry processes, i.e. with little water or solvent.Desiccant may comprise 0.001% to up to 20% of the composition.

A color saturation indicator may be employed.

Oxidative degradation is second only to hydrolysis as a mode ofdecomposition. In contrast to hydrolysis, oxidative mechanisms arecomplex, involving removal of an electropositive atom, radical orelectron or, conversely, addition of an electronegative moiety.Oxidation reactions can be catalyzed by oxygen, heavy metal ions andlight, leading to free radical formation. Free radicals react withoxygen to form peroxy radicals which in turn react with oxidizablecompound to generate additional free radicals to fuel further reactions.Aldehydes, alcohols, phenols, alkaloids and unsaturated fats and oilsare all susceptible to oxidation.

Oxidative gents may be used in the dosage form in effective amounts tofacilitate and encourage oxidative degradation. The dosage form maycomprise 0.001% to up to 20% of an oxidative agent.

Reactions such as oxidation-reduction, ring alteration andpolymerization can be catalyzed or accelerated by exposure to sunlightor artificial light. Energy absorption is greater at lower wavelengthsand, as many as drugs absorb UV light; degradation by low wavelengthradiation is common. Exposure to light almost invariably leads todiscoloration even when chemical transformation is modest or evenundetectable. Agents may be used in effective amounts in the dosage formto encourage photolysis. The dosage form may comprise 001% up to 20% ofa photolysis agent.

Physical stability issues may be promoted by using friable compositionsthat tend to break apart without benefit of the protective primarypackaging, particularly when exposed to ambient conditions. Gels, jelly,gelatin and jam may similarly be particularly suited for this purpose,being difficult to handle outside of packaging, due to viscosity.Jellies and Jams are usually made with pectins and gelatin is a gelatinproduct. A jelly is typically transparent (or largely transparent),whereas a jam is typically more opaque because of the dispersed phase.Jelly is an isotropic gel whereas jam is a dispersion. Both can havesimilar properties.

Moreover, body temperature may further degrade integrity of the dosewhen handling outside of the package is attempted.

Excipients may be used that physically lock up wither the active or thedosage form itself after relatively prolonged exposure to ambientconditions.

It may further be desirable for the dosage form to comprise a dye orstain that can be used to confirm intended administration of the dosageform. The following patents, and specifically their disclosures relatingto such use of a dye or stain, are hereby incorporated by reference:U.S. Pat. No. 7,214,385, and US 20110182807A1.

A “jelly” “Jello-O” gelatin or “jam” type viscous gel may be a desirabledosage form for use with the present invention, because of the inherentdifficulty of removing it and/or storing for subsequent diverted usefrom the primary packaging that may have tracing information. Thisfacilities custody control of the dosage form in connection with thecustody and control platform.

Additionally, gels may be hard to identify outside of packaging, makingthem less desirable for illicit use outside of the custody and controlsystem, and may have inherent physical handling issues.

Films or sheets may be employed. Hot melt extrusion may be a preferredmanufacturing process where the dosage form comprises a desiccant orother moisture sensitive agent intended to held reduce stability of thedosage form outside of the package.

Packaging design may be employed that prevents or tends to prevent theexpulsion of the viscous gel in a single bolus. For example, the packagemay be designed to spray or deliver the gel in multiple streams. Thismay make it difficult to readily collect the dosage form outside of thepackage. In either case if removed the jelly like material will have areduced street value due to a lack of provenance. It is an object of thepresent invention to reduce the street value of a comparable dose ofdrug in a conventional tablet, by 20%, preferably 30% and mostpreferably 50%.

Custody and Control Database

The custody and control database that stores the product identifiers andthe patient to whom the product is dispensed is, in most embodiments, asecure HIPAA complaint system. For example, the patient to whom theproduct is dispensed may be identified using a patient identifier orproxy, not the patient name, the patient name being available to thosepermitted under HIPPA to access it based on the patient identifier orproxy.

Police and law enforcement and dispensing pharmacists (or otherdispensing entity) should have access to the custody and controldatabase. Such access may be used in a variety of scenarios, includingthe checking of discarded packaging.

In certain embodiments, the product manufacturer may have access to thedatabase to enter the product identifier into the custody and controldatabase, so that the entire lifecycle of the drug, e.g., the identityof the pharmacy or distributor to which the drug is provided by theproduct manufacturer, can be captured and tracked in the system.

In certain embodiments, product distributors may have access to thecustody and control database to record their custodianship of theproduct and related product in distribution.

In certain embodiments, drug stores and pharmacies may have access tothe custody and control database to record their receipt of the product(prior to its dispensing to a patient). Such access may be used torecord their custodianship of the product and related product indistribution.

In certain embodiments, repackagers may have access to the custody andcontrol database. Such access may be used to record their custodianshipof the product and related product in distribution.

In certain embodiments, other parties including transportation companiesmay have access to the custody and control database.

In certain embodiments, physicians and prescribing health professionalsmay have access to the custody and control database, whereinprescriptions for drugs are entered for specific patients (therebyproviding a double-check with the recordation of the dispensing of drugby the pharmacist). In addition, it is envisioned that 3^(rd) partypayers may have an interest in the ultimate destination of the drug theyare reimbursing, and accordingly may have access or limited access tothe database.

In certain embodiments, the database may tie to credit agency typereporting and other personal intelligence services. For example, suchdatabases may indicate the likelihood of a patient traveling or being ina certain geographic location. In certain embodiments, law enforcementcan query the database without accessing the actual identity of thepatient.

The database may be operated by the drug manufacturer, a governmentalentity, the pharmacy, a distributor, or other party. It is expresslycontemplated that the database may be combined (or some or all thefeatures of the contemplated database may be incorporated into) thedatabase contemplated by the Drug Quality and Security Act andregulations promulgated pursuant thereto. The Drug Quality and SecurityAct is hereby incorporated herein as if fully stated:www.fda.gov/Drugs/DrugSafety/DrugIntegrityandSupplyChainSecurity/DrugSupplyChainSecurityAct/ucm376829.htm.

Custody and Control Product Identifier

In certain embodiments, the product identifier is resistant to removalor erasure. In other embodiments, the product identifier is placed intwo locations: one accessible to the pharmacist, and one on the insideof the package.

In one embodiment, the product identifier appears on both the outside ofthe primary package (and or secondary package), and within the packagingitself (where it cannot be accessed without opening or otherwisepenetrating the package.

If multiple doses are packed akin to a z-pack, the identifier on thesecondary packaging may identify (directly or through a database) theidentifiers on each unit dose contained therein.

In certain embodiments, the product identifier on secondary packagingcorresponds with, but is not identical to, product identifier(s) on theprimary packaging.

Product identifiers may be in more than two locations on primary orsecondary packaging.

For example, in a well with a topsheet, the identifier may appear onboth the top of the topsheet, and on the bottom of the topsheet. In thisexample, the identifier of the bottom of the topsheet cannot beoverwritten, or crossed out or otherwise obscured without penetratingthe package. In a separate example with a well and topsheet, theidentifier may appear on the topsheet and on the inside surface of thewell.

In the non-limitative example of a viscous gel dosage unit manufacturerin a stick pack, the identifier may be printed on both the inside andoutside of the stick pack material (typically foil).

For the absence of doubt, the primary packaging—typically unit dose—maycomprise any suitable material and design. While wells are discussedextensively in this specification, the primary packaging may compriseany known format, including without limitation, a stick pack, sachet,carton, blister pack, vials, bottles, clamshell packaging, a well,prefilled syringes, inhalers, spray bottles, spray devices and any otherform of primary packaging.

While the preferred embodiment is unit dose, the custody and controlfeatures of the embodiments of the current invention may be used withmulti-dose drug packages as well. In the example of a tablet in ablister pack, the identifier may appear on both sides of the blisterpack foil.

The custody and control identifier may comprise a number, a series ofcharacters, a bar code, QID code, and any other code readable by visual,radio or other methodology.

In addition, as technology advances, the time will come when identifierssuch as but not limited to, ingested identifiers such as RFID tags willbecome available and practical and should be included here.

Jelly type dosage forms have been described in the patent art for usewith dysphagic patients, but not as a system that can or should bemarried with custody control features (see e.g. U.S. Pat. No. 5,932,235,hereby incorporated by reference).

Jelly is an ideal oral dosage unit if combined with the custody controlpouch. Jello-O type or gelatin compositions may similarly be used. A Jamlike composition may be used. If taken properly it is simply squeezedinto (or otherwised placed) the mouth (or other delivery site) and yetit is difficult to prematurely remove from the bodily cavity to which itis delivered. This has particular utility with abuse prone drugs.

Jelly, Jello-O type, jam and gelatin compositions or gels may bedeposited into the primary package, akin to the film by deposit systemdescribed herein. The jelly, gelatin, jam, or gelatin compositions maybe packaged in a well, or a stick pack or other flexible packaging.Flexible packaging is a preferred embodiment for such media.

Liquids may also be used in connection the custody and control featuresof embodiments of the current invention. The liquid may a solution, asuspension or emulsion.

Pectins are strong gel formers, whether in the fruit or fruit juice oradded, depending on pH. Phase angle for jam more than gelatin shown inthe examples below. For the fruit spreads, the phase angle is 15 to 20+,for Santa Cruz organic apricot fruit spread and the Dickinson PurelyFruit Raspbery Spreadables—Much higher than the 1-2 for the jell-o typeproduct. These two are comparable in complex viscosity to the gelatin.The two spreads are highly viscous substances.

The rheology of a tropical gelatin dessert—which may serve as a basecomposition or substrate—is explored in FIGS. 1, 2 and 3 below. Therheology of jam—which may serve as a base composition or substrate—isexplored in FIGS. 4 and 5 below.

Always one must keep in mind that it is the combination of these dosageunits in custody and control with identifiable packaging thatconstitutes the inventive step, as the name of the patient receivingeach individual unit, normally in sequence, that is recorded by thepharmacist, and if need be a dosage unit can thus be traced back to itsoriginal intended user. Tablets and capsules while theoretically beingeach identifiable are presently very difficult and costly to carry anidentification or a buried RFID tag.

In certain embodiments, abuse potential is reduced as measured using themethodologies set forth in the FDA's guidance for industry for“Abuse-Deterrent Opioids-Evaluation and Labeling” (April 2015),available here: www. fda. gov/downloads/Drugs/Guidance s/UCM334743 .pdf

One aspect of the invention is to allow for intermittent movement of thewell substrate as opposed to the continuous movement demanded by the wetcasting method.

Preferred embodiments of the present invention is described herein withreference to FIGS. 1-9 , which schematically show examples of the methodand system of the present invention. However, applicants' invention isnot limited to the particular embodiments/examples shown in the figures.

FIG. 1 shows a roll 1 of pre-formed molds or wells 2 prior to filling bydeposit. In other embodiments, the mold or well 2 may be formed on theproduction line itself from flat roll stock.

FIG. 2 shows a deposit device 3, described in more detail hereinafter,filling a well. The deposit device 3 may be depositing film formercomposition, an active agent composition with optional excipients, or afilm former composition complete with an active agent within it. In FIG.2 , the film former composition, the active agent composition withoptional excipients, or a film former composition complete with anactive agent are all designated generally with the reference numeral 4.

FIG. 3 shows a deposit device 3 filling a well 2 with a film formercomposition 4 a.

FIG. 4 shows a deposit device 3 filling a well 2 with a composition 4 bincluding active ingredient(s) with optional excipients, in particulateform.

In one aspect of the present invention, a film forming composition 4 ais deposited in each well 2 and an active agent composition 4 b isdeposited in each well 2, the active agent composition 4 b beingdifferent than the film forming composition 4 a. The film formingcomposition 4 a and the active agent composition 4 b form an admixturein the well 2. The film forming composition 4 a and the active agentcomposition 4 b may be separately deposited in the well 2 at the sametime, e.g., through two separate deposit devices 3. Alternatively,depositing of the film forming composition 4 a and the active agentcomposition 4 b in each well 2 are carried out sequentially; in thisembodiment, it is preferable but not necessary that the active agentcomposition 4 a is first deposited in the well and then the film formingcomposition 4 b is deposited in the well.

FIG. 5 shows a drying device 5 deploying hot air currents from above theroll of film wells 2 (which have been already filled). In certainembodiments, drying occurs in a drying tunnel (here the tunnel is cutaway for better visibility).

FIG. 6 shows adhesive 6 being applied to well edges, i.e., to areas ofthe bottom sheet 1 outside the wells 2 by an applicator

FIG. 7 shows a roll 1 of wells 2, with films (and drug) 4 deposited,films formed and dried, and guideposts 8 inserted in the ends of theroll 1 of wells 2 for alignment of a top sheet 9 which is placed overthe bottom sheet 1.

FIG. 8 shows a roll 1 of wells 2, with films (and drug) 4 deposited,films formed and dried, guideposts 8, and serration 11 of individualdoses 10 within the roll of wells. Serration can occur in the roll stockprior to deposit of film composition 4 or after the manufacture of film4.

FIG. 9 shows a finished dosage form 10 removed from a roll 1 of wells 2,the breakage lines occurring at the lines of serration 11.

A summary comparison of films made by certain embodiments of the depositmethod of the present invention and films made by wet casting isprovided below.

Parameter/Attribute Wet Cast Oral Soluble Film Deposit Oral Soluble FilmViscosity of film former High Low composition Flowability of film formerLow/None High composition Where Active Drug is Mixed with film formerDeposited separately from added in process prior to coating on substratefilm former composition (or optionally together) Substrate in ContinuousCoating must occur on Deposit in mold/well is not Motion substrate incontinuous continuous (optionally motion continuous) Coating substrateremoval Coating substrate must be Substrate is typically not removed inconversion prior removed; deposited in final to packaging primarypackaging Angle of Flow of film High angle of flow of film Low angle offlow of film former composition former composition former compositionStoke's Law employed to Stoke's Law employed to Stoke's Law hasvirtually maintain drug content maintain drug content no applicationwhere drug is uniformity in film former uniformity in film formerdeposited separately. composition composition Controlled dryingnecessary Controlled drying necessary Controlled drying not for drugcontent uniformity for drug content uniformity necessary for drugcontent uniformity Cutting of film specific size Cutting of filmspecific size Cutting of film not required required to make finalrequired to make final to make final dosage form dosage form dosage formRapid drying required for Rapid drying required for Rapid drying notrequired drug content uniformity? drug content uniformity for drugcontent uniformity Active Drug Waste (loss in High API Waste Low APIWaste process) Coating steps for Bi-layer Typically two separate stepsCan be made in single film of coating deposit step. Cost for Bi-layerTypically expensive (two Marginally longer deposit steps) step.Inexpensive Low Dose Content Potentially challenging Not challengingUniformity Air bubbles, voids and Air bubbles, voids and Air bubbles,voids and surface defects create surface defects create surface defectsdo not create content uniformity issues content uniformity issuescontent uniformity issues Separation of incompatible Difficult Simpleusing separate drug actives in a deposit steps combination productLiquid suspension, solution, Can be deposited efficiently Deposition isnot difficult. emulsion, gel, jellies, jams, but cannot be cast mousse,pudding, gelatin, etc.

One aspect of the present invention is to enable film formulations whichwould have not have adequate mechanical properties for traditional oralsoluble film manufacturing, i.e. ability to wind into a roll, ability tobe trimmed and covered, ability to be released from substrate, andability to be converted in a conventional film packaging machine (e.g. aDoyen Medipharm machine). For example, a formulation that hasinsufficient tensile strength for conventional conversion, or aformulation that has propensity for elongation under stress, would beunable to be converted using conventional means but is able to bemanufactured using the deposit method.

The drug that is being deposited may be in the form of a powder or asolution in which case the drug solution in the bulk tank from which itis being deposited into wells in aliquots does not have to be stirred.However, it may also be a suspension of fine drug particles that may becontinuously and vigorously stirred while the suspension is beingdeposited in aliquots into wells. Continuous stirring is generally notpossible with viscous drug suspensions such as those used informulations for continuous coating due to the induction of air into themix which causes film defects and precludes collection of good anduniform product. In the deposit method, the low viscosity generally doesnot allow air bubbles to form in the film as they are immediatelydissipated as the deposited liquid flows into the well as a thin layer.

Applicants teach against the fundamental theme of prior film art (Yanget al, Horstman, etc), namely, the use of high viscosity to (i) preventmigration of the active and preserve uniformity of dose content in themixing stage, (ii) enable the required coating thickness of the filmcomposition, and (iii) prevent migration of the active and preservecontent uniformity in the drying stage. Instead, high viscosity (andsurface tension) here work contrary to (i) the ability to deposit thefilm former composition into the well or mold, and (ii) the ability ofthe film former to flow (and reasonably rapidly and without mechanicalintervention) into a film within the well or mold.

Deposit of a high viscosity film former composition such as those taughtby Yang et al. in a well or mold will not generally result in a film atall, but rather simply a dollop-type shape of film former absentphysical, mechanical intervention to spread the film former into a film(like a doctor blade, or other coating apparatus). Viscosity and surfacetension simply prevent such compositions from flow, let alone sufficientflow to form a film.

It is important to note that to accurately dose and spread film formerin a well, a relatively low viscosity is required (and surface tension),otherwise the material will refuse to spread in the well and simple forma dollop of material in part of the well.

Moreover, the embodiments where the drug active is separately depositedin the well or mold, high viscosity and lack of wetting can actuallyinterfere with mixing of the drug active into the film matrix, therebypreventing adequate mixing of drug and film former composition fromoccurring.

High viscosity is also not needed to enable coating thickness of thecomposition; in the deposit method of the present invention the filmcomposition can be readily deposited as high as the sides of the well ormold.

Film former and active are metered into the wells either singly or bymultiple metering devices.

It is important to note that to accurately dose and spread film formerin a well, a relatively viscosity low is required (and surface tension),otherwise the material will refuse to wet and spread in the well andsimply form a dollop of material in part of the well.

Preferably, the after deposit, the film former composition will flowinto a film in a well or mold within ninety seconds, preferably withinsixty seconds, more preferably within twenty seconds, even morepreferably within five seconds, and most preferably within one second.By flow into a film, Applicants mean that the film former compositionwill either reach the ends of the mold/well, or otherwise cease to flow.

This time is important as it will impact production line speed. Outputof course may be improved by using a bank of feeders (filling multiplewells forward and horizontally at one time).

Both viscosity and surface tension are connected theoretically tointer-molecular forces, but they are still very different concepts.

Shear Stress is a force that acts on a fluid to cause flow and theviscosity determines velocity gradient. Viscosity is an intrinsicproperty of the fluid itself. Viscosity is the ratio of the shear stresstensor to the rate of deformation tensor. Roughly speaking, viscositydetermines how momentum is transported through a fluid during flow, asit is a measure of resistance to flow.

Contact angle acts not inside the substance, but only on its interfacialboundary with substance of another phase, even if nothing moves. It isnot a property of the substance itself, but of a pair of these phasesmeeting at the boundary. Often the expression “contact angle of water”is used; but what is meant is contact angle of the pair water-air.Combinations water-glass or water-oil have different value of contactangle. Roughly speaking, contact angle says how much energy ofinteraction is stored when two chemical species are in mutual contact,even in equilibrium.

One way to think about the effective flowability of a film formercomposition for a given type of surface, is Young's equation. A drop ofliquid when placed on a flat, homogenous solid surface comes toequilibrium, assuming a shape which minimizes the total free energy ofthe system. The angle between the liquid and the solid is called thecontact angle, the angle being measured through the liquid. The contactangle may be calculated if the surface tension and interfacial tensionare known, using Young's equation (seeen.wikipedia.org/wiki/Wetting#Ideal_solid_surfaces , which isincorporated by reference as if fully stated herein, as retrieved onMar. 26, 2017). For certain embodiments of the present invention,surface tension and interfacial tension are minimized to reduce thecontact angle of the system. To wet the substrate well, the contactangle must be <90°.

One way to think about the rate of flow or spreading of the composition,is Tanner's law. Tanner's law teaches that the rate of spreading of adroplet is related inversely to the viscosity of the droplet. See Bonnet al, “Wetting and Spreading” (hereby incorporated by reference as iffull set forth here in, and Krishnakumar, “Wetting and SpreadingPhenomena, available here:guava.physics.uiuc.edu/˜nigel/courses/563/Essays_2010/PDF/Krishnakumar.pdfand similarly hereby incorporated by reference as if fully set forthherein).

The preceding teaches away from Yang et al, wherein the film compositionyields a high contact angle on the substrate, which allows forrelatively thick non-flowing compositions. In fact, wet cast filmcoatings are so thick and unflowable, Watson has taken the position inits Suboxone ANDA litigation that its film coating should be understoodto be a solid immediately after coating: “The physical evidencedemonstrates that Watson's casting dispersion forms a viscolelasticsolid when the forces of mixing and pumping cease, which happens beforethe initiation of drying . . . . The inspection video demonstrates that:(1) by the time Watson's casting dispersion travels up a steep inclinefor 30 seconds, and prior to any drying, it has already gainedsufficient structure to “lock-in” and prevent migration of the activesuch that the casting dispersion does not flow backwards down theincline , as it would if it were a viscoelastic liquid; (2) Watson'sfilms are cast as in discrete lanes at the width of the final film,which would not be possible if the casting dispersion were aviscoelastic liquid...” From Document 186, pp. 10-11, Case1:14-cv-01574-RGA (District Court for Delaware). Thus Watson is statingto the Court that its film composition is simply not flowable at all,absent the mechanical intervention of the coating apparatus

Film compositions of the present invention may be non-Newtonian orNewtonian. It should be noted that in the preferred embodiment, nomechanical force is applied to the film composition after deposit intothe mold or well to encourage spreading/flowing of the film formercomposition. Accordingly, shear thinning or pseudo plastic attributes donot materially effect flowability in the well or mold since there isgenerally no mechanical source of shear stress other than gravity toaffect a reduction in viscosity (as we would see in a coatingapparatus).

It is contemplated in certain embodiments that shear force may beachieved by pressurized delivery of film former composition into thewell (such shear being affected by the impact of the film formercomposition against the well). However, there are practical limitationson how much shear can be achieved in this manner with substantialabsence of splatter outside of the well. Nozzle design can be optimizedto reduce or mitigate splatter.

Film compositions of the present invention may have little or no yieldstress. In certain embodiments, film compositions of the presentinvention will have insufficient yield stress to prevent flow on anincline greater than 45%, greater than 25% or even greater than 10%. Incertain embodiments, the film composition of the present invention willhave a yield stress <50 pa, preferably <30 pa, most preferably <15 pa.

The focus of the present invention teaches away from the thinking in thecast film art to use high yield stress to prevent sedimentation of drugparticles and other components.

Continuous or Stuttered Manufacture

Embodiments of the present invention may employ continuous manufactureor stuttered (intermittent) manufacture.

In conventional wet casting, the substrate must be coated continuously.There is time (and waste) associated with bringing the coating processonline to operating parameters with appropriate coating thickness. As apractical matter, the process must be continuous. This continuouscoating typically implies long drying ovens.

Certain embodiments of the deposit method allow for a stutteredmanufacturing process. One or more molds/wells is filled. At this time,the mold/well rollstock is stationary or moving (relative to the fillerapparatus). After filling, the mold/well can be moved to a dryer. Incertain embodiments, the filler may move with the mold/well so as tohave no relative speed as between them during filling. Again, the moldsor wells may continuously move through the dryer or it may be stationaryin the dryer. The dryer apparatus may also be deployed after filling ina single place (i.e. without the mold/well moving).

In many embodiments, the deposit of film former composition and drug(and ensuing flowing into a wet film in the mold/well) is faster thanthe drying stage. Because deposit is non-continuous, in someembodiments, the mold/wells may be in stage blocks that can be placedinto an oven on multiple levels. This allows for a small dryer footprintto accommodate relatively high production.

The stuttered option for deposit allows for a very efficientmanufacturing in terms of footprint. Skilled artisans will appreciatethe various configurations for deposit, drying, and packaging overlay onthe molds/wells. A circular or other return layout between filler anddryer may be employed where a follow deposit is desired to be made to aninitial dried film layer.

Methods of Deposit

Generally, the materials will be deposited in the well or mold using aflowmeter enabled feeder (any suitable flowmeter and feeder may beemployed). The flowmeter may measure mass and/or volumetric flow rate ofa liquid or solid. K-tron is a non-limitative example of a suitablefeeder. Any suitable apparatus that can reliability deposit Filmerformer composition or drug may be employed.

Apart from gravity feed, pumps may be employed to feed the material intothe well. Speed of deposit is important for line speed/product output.Moreover, it may be desirable to inject material into the mold or wellwith some additional force beyond gravitational force.

A bank of feeders may be employed to allow for a number of wells/moldsacross (and forwards) to be simultaneously. Optionally, the bank offeeders may source from a single mother tank.

Where the drug is deposited separately, multiple feeders may beemployed: one to supply an active drug (or drug combination) (optionallywith one or more suitable excipients), and one to supply the film formercomposition.

If the active drug is a particle, the active drug may be delivered indry powder form, or in solution (where soluble), suspension or emulsion.One advantage of dry powder form is to avoid the time during which thedrug active is in contact with liquid (which can avoid problems withcrystallization, drug stability, and the degradation of taste masking orcontrolled release systems).

Where the drug is soluble, certain embodiments may use a pH for the drugsolution optimized for solubility (where pH buffer of the film formercomposition uses a different, stronger buffer to control the ultimate pHof the dosage form). The drug may be solubilized in any appropriatepolar or non-polar solvent.

One advantage of a solution, suspension or emulsion, is to promotemixing of the pharmaceutically active agent with the film formercomposition, though it is demonstrated in examples below that dryparticles can be adequately mixed with separately metered film formercompositions.

The feeders may employ nozzles that are optimized to promote mixing. Forexample, the nozzle may be selected to broadly disperse material in thewell. The nozzle may be aimed to initiate flow in the well or mold.Where the drug is administered separately, the nozzle depositing thedrug and the nozzle depositing the film former composition may be aimedin a complimentary fashion to promote mixing of the two. As anon-limitative example, the nozzles may direct the flow of the filmformer composition and drug in opposite directions. Nozzles may have adesign to encourage mixing. In addition, nozzles may be used that have aspray pattern which is matched or otherwise calibrated to the welldimension.

Where the drug is administered separately from the film formercomposition, the two may be deposited in sequence, or contemporaneously(in which case the deposit rates may be calibrated in terms of time), ormetered in a rotating sequence (for example and without limitation, filmformer composition, drug: drug, film former composition).

Where delivered separately, each of the film former composition and thedrug (be it in particulate, solution, suspension, emulsion etc) mayoptionally be paired with any suitable excipient.

Separate administration of film former composition from drug is thepreferred embodiment. First, the viscosities of a film formercomposition to resist sedimentation of the active would be too high forthe film-by-deposit method of the present invention. Second, evensoluble drugs may tend to come out of solubility in the film formercomposition, due to the relative low levels of solvent, interaction withother materials in the film former composition, and other chemicalprocesses. Generally, greater control and reliability of target dosedeposit is associated with separate administration of drug.

Drugs may be separately and sequentially deposited in the case ofincompatible drugs. For example, multiple layers may deposited, eachwith a different active. In certain embodiments, the second layer isdeposited after the preceding lawyer has been dried. In some instances,the active and the film former and the excipients could all be in onemix and dispensed simultaneously through a single deposition from onedeposer. In embodiments in which the second layer deposited after thefirst layer is dried, it could be on top and include, withoutlimitation, active in sustained release form, taste masking, absorptionenhancers, pH modifiers and other modifiers such as an acid and base toproduce effervescence. When introduced however, with things likecoloring the mix, the top could become the bottom re the patientdirections.

It may be desirable to heat the film former composition to promoteflowability prior to, or after deposited in the mold or well. Attentionmust be paid to degradation temperature, and the sustained temperatureshould not exceed the drugs's known degradation temperature. Temperatureincrease will tend to decrease viscosity and surface tension providedthat the solvent is not permitted to escape (or otherwise notreplenished).

The Well or Mold

In this application, we use the terms well and mold interchangeably.

The well or mold will generally be of suitable depth to contain the wetheight of the desired film composition. As a practical matter, the filmtends to reduce in thickness when dried. The well or mold may bepretreated with silicone, hydrophobic agents, or and other suitablematerial that promotes flow of the film composition and/or promotesrelease of the final dry film from the well or mold.

Round shapes of the well or mold are desirable, but non limiting, toform a round film. Circular shapes may be particularly desirable butsquare or rectangular forms are also possible. In the case of circularshapes, the film composition can be deposited in the center and flowoutward. Any regular or irregular polygonal shape may also be possible.The mold or well may also be shaped for form three dimensionalattributes on the bottom of the film.

The sides of the well or mold may be perpendicular, angled (outward fromthe planar bottom surface).

In certain embodiments, the well or mold is sufficiently flexible toallow a consumer to readily push the bottom of the well or mold up topresent the film for easy access by the patient.

The well or mold material must be able to withstand drying temperaturesof the drying process.

In certain embodiments, the mold or well is formed using mechanicaltools (including without limitation, dies or stamps) as part of thecontinuous production process. For example the process may begin with asuitable, flexible rollstock in which the required wells are formed by adie tooling, such formation occurring prior to the deposit step inproduction.

In certain embodiments, the well or mold is sufficiently flexible andshallow enough to allow for the well or mold, after deposit, drying, andapplication of top sheet, to be rolled onto itself after drying. Inother embodiments, the wells or molds or cut in blocks and stacked afterapplication of the top sheet.

In most embodiments, the area of the mold or well defines the dimensionsof the film. The mold or well is of fixed size. Generally, the mold orwell with have a deposit surface of 2 square inches or less, preferably1.5 square inches or less. Larger size are possible smaller sizes arepreferred for comfort (in oral use), as well as to speed flow of thefilm composition to ultimate dimensions (i.e. a shorter distance totravel).

In certain embodiments, the molds or wells are fixed and the dried filmsare removed from said molds or wells which can then be reused.

In certain embodiments, the well or mold is made of metal foil, e.g.,aluminum foil, or plastics, and combinations. Suitable materials mayinclude, without limitation, polyvinyl chloride (PVC), polyethylene(PE), polypropylene (PP), polyester (PET), Polyvinylidene chloride(PVDC), Polychlorotrifluoro ethylene (PCTFE), cyclic olefin copolymers(COC) or polymers (COP), monomer ethylene (LDPE), Aclar, paper aluminumcombinations, paper/PET/aluminum laminates, and other aluminum basedlaminates.

The Drying Process

Typically, the film is dried in the well or mold. Drying can occur withlittle consideration to migration of drug, unlike traditional film wetcasting. The only practical consideration relates to enabling suitablemixing of the drug (in embodiments where the drug is separatelyadministered from the film forming composition) into the film matrix.

Generally, consideration is given to speed, energy use and efficiency ofdrying, sufficient evacuation of solvent, and minimizing visibleimperfections on the film.

Another important distinction, is drying time. In conventional wetcasting, the aim is to rapidly dry the film to prevent migration of theactive. For example, U.S. '277 claim 1 describes “rapidly increasing theviscosity of said polymer matrix upon initiation of drying within aboutthe first 4 minutes to maintain said uniform distribution of saidpharmaceutical active by locking-in or substantially preventingmigration of said pharmaceutical active.”

Because the present invention meters the desired drug loading, there isno concern for agglomeration of drug from a content uniformityperspective. This allows for longer drying times. Such longer dryingtimes can serve a variety of purposes, and can be particularly useful inconnection thicker films or for actives that are particularly heatsensitive.

At the same time, more rapid drying times can be effected, withoutconcern for disruptions to the top of the film surface.

Since cast film requires viscosity rapidly for uniformity of dosage,specific drying is described, oriented towards early bottom drying toprevent volatile release of solvent and disruption of uniformity. On theother hand, the system herein described does not have that requirementand hence simplified top drying, not limited to air, infrared etc. isvery workable. Jellies, jams and gelatin may not require drying.

Taste Masking

All currently known (and future) methods of taste masking may beemployed, including flavors, sweeteners, bitter masking agents, coatedparticles, ion exchange resins and other methods. A significantadvantage of the present method is that the drug residence time can beminimized.

For example, where the drug is deposited separately from the filmformer, the drug can be completely without solvent. As a non-limitativeexample, drug in an ion exchange complex can be metered into the well,or coated drug particles. This means that the only exposure to water (orother solvent) in the film forming process is the brief period when thedrug is mixed with the film former composition until the solvent isdried.

Preferably, taste masked particles have a particle size with a diameterno greater than the dried height of the film itself. Consideration mayalso be given to mouthfeel. Preferably for mouthfeel particle size isbelow 300 microns, preferably below 200 microns most preferably below100 microns.

It is noted that the deposit method of making films taught herein offersa particular advantage for taste masking, namely, the ability tominimize the time that controlled release drug particles (or complexes)are subject to a solvent.

In the method where the drug active is deposited separately from thefilm former composition, the drug particles (or complexes) are exposedto the solvent used to hydrate the film former for the very brief periodbetween deposit of the drug particles (or complexes) and the time ittakes to substantially remove the solvent by drying. This can have alsoadvantages even where neat drug is used (e.g. to avoid a drug frompartially solubilizing in the solvent and then crystallizing).

Accordingly, total residence time of the drug with liquid solvent may beless than fifteen minutes, preferably less than ten minutes, morepreferably less than five minutes, and most preferably less than twominutes. Such low residence times are also of utility with taste maskedor controlled release drug particles or complexes.

Controlled Release

The term “controlled release” is intended to mean the release of activeat a pre-selected or desired rate. This rate will vary depending uponthe application. Desirable rates include fast or immediate releaseprofiles as well as delayed, sustained or sequential release.Combinations of release patterns, such as initial spiked releasefollowed by lower levels of sustained release of active arecontemplated. Pulsed drug releases are also contemplated. A non limitingexample would be where immediate acting drug is separately depositedtogether with or separate from the film former and a second or thirddeposit of drug with a differing release pattern is added.

The polymers that are chosen for the films of the present invention mayalso be chosen to allow for controlled disintegration of the active.This may be achieved by providing a substantially water insoluble filmthat incorporates an active that will be released from the film overtime. This may be accomplished by incorporating a variety of differentsoluble or insoluble polymers and may also include biodegradablepolymers in combination. Alternatively, coated controlled release activeparticles may be incorporated into a readily soluble film matrix toachieve the controlled release property of the active inside thedigestive system upon consumption.

Films that provide a controlled release of the active are particularlyuseful for buccal, gingival, sublingual and vaginal applications. Thefilms of the present invention are particularly useful where mucosalmembranes or mucosal fluid is present due to their ability to readilywet and adhere to these areas. In addition, this invention would allowfor a barrier layer to be metered in the well at some time after theinitial well contents have solidified, thus making a buccal/barrierproduct. Such barrier layer (soluble or insoluble) may also be depositedfirst in certain embodiments.

The convenience of administering a single dose of a medication whichreleases active ingredients in a controlled fashion over an extendedperiod of time as opposed to the administration of a number of singledoses at regular intervals has long been recognized in thepharmaceutical arts. The advantage to the patient and clinician inhaving consistent and uniform blood levels of medication over anextended period of time are likewise recognized. The advantages of avariety of sustained release dosage forms are well known. However, thepreparation of a film that provides the controlled release of an activehas advantages in addition to those well-known for controlled releasetablets. For example, thin films are difficult to inadvertently aspirateand provide an increased patient compliance because they need not beswallowed like a tablet. Moreover, certain embodiments of the inventivefilms are designed to adhere to the buccal cavity and tongue, where theycontrollably dissolve. Furthermore, thin films may not be crushed in themanner of controlled release tablets which is a problem leading to abuseof drugs such as Oxycontin. Furthermore, as mentioned the sequentialnumbering of the unit dose wells allows for identification of a sourceof the abusive drugs, providing the pharmacist notes the identificationindicia during dispensing.

The actives employed in the present invention may be incorporated intothe film compositions of the present invention in a controlled releaseform. For example, particles of drug may be coated with polymers such asethyl cellulose or polymethacrylate, commercially available under brandnames such as Aquacoat ECD and Eudragit E-100, respectively. Solutionsof drug may also be absorbed on such polymer materials and incorporatedinto the inventive film compositions. Other components such as fats andwaxes, as well as sweeteners and/or flavors may also be employed in suchcontrolled release compositions.

Film Thickness

Films are typically understood to be up to 10 mils in thickness (finalproduct as dried), and above ten mils the product is referred to in asheet. For ease of reference, references herein to film are understoodto apply film (sheet) both up to, and beyond 10 mils in thickness. Filmsof the present invention may be 1-200 mils, preferably 5-20 mils, mostpreferably 5 to 15 mils. Thickness may be augmented above the foregoingthicknesses, including without limitation, for dermal use of the endproduct.

Guided Placement

The mold or well becomes the bottom of the final package and onlyrequires the guided placement of a top sheet which completes the packageand the dose unit is merely cut or weakened from the dosage next to it.By guided placement is meant that markers, physical or printed align thetop sheet so that cutting of the final unit dosage unit aligns readilywith the cutter or perforator. In addition, full labeling requirementsmay be resident on the top sheet and bottom wells.

Content Uniformity

The most substantial problem in cast films is the difficulty to have auniform dosage in a film which is cast with the active diluted by alarge number of film formers and other additives plus a time profile forcasting plus the fact that true uniformity is never present in all partsof a cast film. Hence a cast film is dependent on the size of the filmto meet FDA guidelines.

Ideally, as we will see the film forming materials and the active shouldbe depositeded from a separate source and into a well of a fixed size.

An aspect of the present invention is adequate mixing of the drug andfilm former composition, not from the perspective of uniformdistribution of drug in the film, but rather adequately containing thedose of the drug within the final dried film matrix. This means thatsubstantially all of the drug is contained within the film matrix inmost embodiments, meaning the drug is substantially subsumed within thefilm. However, in certain embodiments, the drug will be deposited andremain on the top surface of the film, or remain on the bottom surfaceof the film. A polymeric binder may be used when the drug is depositedto ensure that it remains adhered to the film.

Mechanical intervention (Absence of)

Thematically, the Applicants teach low viscosity of the film formercomposition to form a film in the mold or well. This system teaches awayfrom the high viscosities relied upon for content uniformity equilibriumin cast film.

This patent teaches against the main fundamental of prior film art,namely, the use of high viscosity to prevent migration of the active andpreserve uniformity of dose content. Instead, high viscosity here workscontrary to the deposition of the film former's dispersion in the well.Accuracy of the active is instead preserved by the direct depositioninto the well contains the film former.

By mechanical intervention, we mean physical contact with the filmcomposition to spread the film composition, e.g. a three roll coatingapparatus, a doctor blade, or equivalent coating technique.

The high viscosity (and high surface and interfacial tensions) of theprior art (see Watson reference to non-flowing solid/film), requiredmechanical intervention (via the coating apparatus) to apply as a film.The film compositions of the prior art simply lack the spreading or flowcharacteristics to make films deposited in wells.

However, it is contemplated that non mechanical compressed air and/orvibration and/or brief ultrasound may be employed to encourage flow ofthe film composition into a film in the mold or well or surface activeagents to reduce surface tension or substrates to reduce contact angleto promote wetting and spreading of film composition.

Printing/Embossing

Once the film is dry, it is possible to print or emboss an identifier onthe film dosage form. For printing, individual print heads are typicallyrequired. One advantage of the current invention is that printing can betargeted and calibrated in a precise location on the film. Also the wellmay have a chevron such that it leaves an imprint identity on the driedfilm.

Multi-layer Films

Multi layer films are possible with this methodology simply by additiondepositions of actives, or additional film compositions in themanufacturing process. For example, a semi insoluble (or insoluble)backing layer may be separately deposited on a deposited film. This maybe done after the first layer is dried, or where density and miscibilitywill permit separate deposit on non-dried layers, on a non-dried layer.Similarly, a special layer of muco-adhesive, permeation enhancers, orother excipients disclosed herein may be deposited separately wheredesired.

Covering the Mold or Well

It is contemplated that the mold or well will be covered and sealed aspart of a continuous manufacturing process. It is important then thatconsideration be given relative to ambient humidity prior to sealing themold or well to avoid bringing excess moisture into the package. It maybe desirable to cool the film containing well or mold, or use othermethod (compressed air, nitrogen or other gas) to reduced humidity priorto packaging.

Various forms of guided placement may be employed to ensure alignment ofthe mold or well with the top covering. In other embodiments, guidedplacement is not needed, particularly where the top covering is gangprinted.

The top covering will typically be foil, aclar, or other suitable sheetlike material with suitable barrier properties to ensure stability ofthe product for the intended area of use (see ICH global guidelines).

The final package may be child resistant. The molds or wells may bejoined together in a group of packages or may be separated. Suchseparation may occur at the time of filling/deposit or later, i.e. afterdrying.

The Dried Film

Thematically, film formation by deposit presents much more flexibilitythan conventional wet casting. This is because in conventional wetcasting, uniform distribution of active within the film is necessary sothat when cut into final pieces the individual film doses will meet drugcontent label claims.

In contrast, here the desired level of drug is accurately metered intothe mold or well along with the film former composition. Drug migrationor agglomeration is not really an issue.

The dried film must have only minimal mechanical strength to allow it tobe released from the mold or well. A given film formulation's propensityto elongation is acceptable. Tensile strength and elasticity may beminimal.

The dried film must simply be strong enough for release and use by theconsumer.

Issues like surface mottle, or voids do not represent drug contentdefects, and so are judged on the basis of consumer acceptability.

The dried film of the present invention preferably has less than 10%variability in height (measured from the thickest portion of the film tothe thinnest portion, measured vertically). In certain embodiments,additional variability may be acceptable or preferred for a wedged ortapered shape.

Preferably, substantially all of the drug is contained within the driedfilm matrix in most embodiments. However, in certain embodiments, thedrug will be deposited and remain on the top surface of the film, orremain on the bottom surface of the film.

Pre-Releasing the Film

In some embodiments, it may be desirable to take steps to pre-releasethe film from the bottom of the mold or well (such pre-release may be inwhole or in part). For example, a roller may be employed with a surfacethat promotes release of the film from the bottom of the mold or well.This step may occur prior to, or after, the covering is placed in top ofthe mold or the well. The purpose is to make it easier for the patientto remove the film from the mold or well for use. Vacuum may also beemployed for this purpose.

Film-Forming Polymers

The non limiting polymer may be water soluble, water swellable, waterinsoluble, or a combination of one or more either water soluble, waterswellable or water insoluble polymers. The polymer may include celluloseor a cellulose derivative. Specific examples of useful water solublepolymers include, but are not limited to, pullulan, hydroxypropylmethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium aginate,polyethylene glycol, xanthan gum, tragancanth gum, guar gum, acacia gum,arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinylcopolymers, starch, gelatin, and combinations thereof. Specific examplesof useful water insoluble polymers include, but are not limited to,ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetatephthalate, hydroxypropyl methyl cellulose phthalate and combinationsthereof.

As used herein the phrase “water soluble polymer” and variants thereofrefer to a polymer that is at least partially soluble in water, anddesirably fully or predominantly soluble in water, or absorbs water.Polymers that absorb water are often referred to as being waterswellable polymers. The materials useful with the present invention maybe water soluble or water swellable at room temperature and othertemperatures, such as temperatures exceeding room temperature. Moreover,the materials may be water soluble or water swellable at pressures lessthan atmospheric pressure. Desirably, the water soluble polymers arewater soluble or water swellable having at least 20 percent by weightwater uptake. Water swellable polymers having a 25 or greater percent byweight water uptake are also useful. Films or dosage forms of thepresent invention formed from such water soluble polymers are desirablysufficiently water soluble to be dissolvable upon contact with bodilyfluids.

Other polymers useful for incorporation into the films of the presentinvention include, but are not limited to, biodegradable polymers,copolymers, block polymers and combinations thereof. Among the knownuseful polymers or polymer classes which meet the above criteria are:poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polydioxanoes,polyoxalates, poly(.alpha.-esters), polyanhydrides, polyacetates,polycaprolactones, poly(orthoesters), polyamino acids,polyaminocarbonates, polyurethanes, polycarbonates, polyamides,poly(alkyl cyanoacrylates), and mixtures and copolymers thereof.Additional useful polymers include, stereopolymers of L-and D-lacticacid, copolymers of bis(p-carboxyphenoxy)propane acid and sebacic acid,sebacic acid copolymers, copolymers of caprolactone, poly(lacticacid)/poly(glycolic acid)/polyethyleneglycol copolymers, copolymers ofpolyurethane and (poly(lactic acid), copolymers of polyurethane andpoly(lactic acid), copolymers of .alpha.-amino acids, copolymers of.alpha.-amino acids and caproic acid, copolymers of .alpha.-benzylglutamate and polyethylene glycol, copolymers of succinate andpoly(glycols), polyphosphazene, polyhydroxy-alkanoates and mixturesthereof. Binary and ternary systems are contemplated.

Other specific, but non limiting, polymers useful include those marketedunder the Medisorb and Biodel trademarks. The Medisorb materials aremarketed by the Dupont Company of Wilmington, Del. and are genericallyidentified as a “lactide/glycolide co-polymer” containing “propanoicacid, 2-hydroxy-polymer with hydroxy-polymer with hydroxyacetic acid.”Four such polymers include lactide/glycolide 100 L, believed to be 100%lactide having a melting point within the range of 338°-347° F.(170°-175° C.); lactide/glycolide 100 L, believed to be 100% glycolidehaving a melting point within the range of 437°-455° F. (225°-235° C.);lactide/glycolide 85/15, believed to be 85% lactide and 15% glycolidewith a melting point within the range of 338°-347° F. (170°-175° C.);and lactide/glycolide 50/50, believed to be a copolymer of 50% lactideand 50% glycolide with a melting point within the range of 338°-347° F.(170°-175° C.).

The Biodel materials represent a family of various polyanhydrides whichdiffer chemically.

Generally, lower molecular weight polymer grades will be favored forcertain embodiments of the present invention, as they will make lowerviscosity film former compositions.

Such lower molecular weight grades will generally disintegrate fasterthan higher molecular weight grades. Where longer disintegration timesare desired, it may be desirable to include non-water soluble polymers.

Suitable Excipients

Any suitable excipient known in the art may be using in compositions ofthe present invention. Apart from film formers, a non-limiting listincludes, pH buffers, permeation enhancers, surfactants, viscosityreducing agents, wetting agents, de-gassing agents, gassing agents,flavors, bitter masking agents, plasticizers, anti-caking agents,co-solvents, antioxidants and any other known excipient.

Excipients may be included in sufficient or effective amounts.

As discussed above, excipients may be added with the film formercomposition, or the drug (where the two are deposited separately).

Solvents

The following is a non-limiting list of solvents that may be employed:water, ethanol, acetone, DMSO, isopropanol, glycerol, propylene glycol,propylene carbonate, ethyl acetate, d-limonene.

pH Buffers

Buffering agents may be used to control pH (acidic or base), includingwithout limitation, sodium bicarbonate, potassium bicarbonate, sodiumcarbonate, potassium carbonate, calcium carbonate, dipotassiumphosphate, potassium citrate, sodium phosphate, Formic Acid/SodiumFormate, Hydrogen Chloride/Potassium Chloride, HydrogenChloride/Glycine, Hydrogen Chloride/Potassium Hydrogen Phthalate, CitricAcid/Sodium Citrate, Acetic Acid/Sodium Acetate, Citric Acid/DisodiumHydrogen Phosphate, Citric Acid/Trisodium Citrate Dihydrate, etc, andany other such buffer system.

The buffer system may be designed to dynamically control the pH of theproduct taking into consideration the effect of saliva during use, i.e.,a dynamic buffer system. Non limitative, examples of buffer systems toobtain a pH include dibasic sodium phosphate and monobasic sodiumphosphate. Both are FDA accepted buffer materials used and listed in theinactive ingredients list.

For example, for a pH of 7, the ratio of monobasic/dibasic can be4.6/8.6; for a pH of 5 the ratio of monobasic/dibasic can be 1.9/11.9;and for a pH of 8.0 the ratio of monobasic/dibasic can be 0.6/13.4.These are mathematically calculated buffer numbers and will need to beadjusted according to the other ingredients added to the formula.

They also need to be adjusted for the length of time designed for thedissolution of the dosage unit on the buccal mucosa since saliva can beof a ph of about 6.8 but as it is made in larger amounts in the mouththe ph of saliva can sometimes become more basic. Thus, this dynamicbuffer range is adjusted in the dosage unit by the amount s of thebuffer system since saliva is freshly renewable in the mouth. See FuiszU.S. Patent Application Publication Nos. 2009/0098192 A1 and US2011/0318390 A1 discussing dynamic buffering and incorporated herein byreference. The dynamic buffer systems of the present invention may beacidic or basic.

Surfactants

Surfactants may be useful in connection with the present invention toreduce surface tension. Reducing surface tension is helpful to promoteflowability of the film composition (see Young Equation discussedabove), and may also be useful to promote mixing of the film formercomposition with separately added drug.

Non limiting surfactants may include non-ionic surfactants, like polyolesters (e.g. glycol or glycerol esters, sorbitan derivatives);polyoxyethylene esters (e.g. polyethylene glycol (the “PEGs”; andpoloxamers. Common ionic surfactants include ethers of fatty alcohols.

Any suitable surfactant may be employed.

In the approach of Yang et al, too much surfactant will create a productwith a contact angle that is too low (Young's Equation) for coating onthe substrate. Here, the formulator will want to use more surfactant todecrease the contact angle and promote flowability.

Permeation Enhancers

The film made by deposit may comprise one or more penetration agents,i.e., a substance that enhances absorption through the mucosa, mucosalcoating and epithelium (otherwise known (see U.S. Patent ApplicationPublication No. 2006/0257463 A1, the content of which is incorporatedherein by reference) as a “penetration enhancer” or “permeabilityenhancer”). The penetration agent may comprise but is not limited topolyethylene glycol (PEG), diethylene glycol monoethyl ether(Transcutol), 23-lauryl ether, aprotinin, azone, benzalkomin chloride,cetylperidium chloride, cetylmethylammonium bromide, dextran sulfate,lauric acid, lauric acid/propylene glycol, lysophosphatilcholine,menthol, methoxysalicylate, oleic acid, phosphaidylcholine,polyoxyethylene, polysorbate 80, sodium EDTA, sodium glycholated, sodiumglycodeoxycholate, sodium lauryl sulfate, sodium salicylate, sodiumtaurocholate, sodium taurodeoxycholate, sulfoxides, and various alkylglycosides or, as described in U.S. Patent Application Publication No.2006/0257463, bile salts, such as sodium deoxycholate, sodiumglycodeoxycholate, sodium taurocholate and sodium glycocholate,surfactants such as sodium lauryl sulfate, polysorbate 80, laureth-9,benzalkonium chloride, cetylpyridinium chloride and polyoxyethylenemonoalkyl ethers such as the BRIJ.® and MYRJ.® series, benzoic acids,such as sodium salicylate and methoxy salicylate, fatty acids, such aslauric acid, oleic acid, undecanoic acid and methyl oleate, fattyalcohols, such as octanol and nonanol, laurocapram, the polyols,propylene glycol and glycerin, cyclodextrins, the sulfoxides, such asdimethyl sulfoxide and dodecyl methyl sulfoxide, the terpenes, such asmenthol, thymol and limonene, urea, chitosan and other natural andsynthetic polymers. Preferably, the penetration agent is a polyol, e.g.,polyethylene glycol (PEG), glycerin, maltitol, sorbitol etc. ordiethylene glycol monoethyl ether (Transcutol).

Preferably, the dried film composition may comprise 0.01% to 10%permeation enhancer by mass, more preferably 0.1% to 5%.

Viscosity Reducing Agents Various agents may be employed to reducedviscosity. In particular and without limitation, hydrophobic salts mayserve to reduce viscosity, which is of use in connection with the filmformer composition. Without limitation, the following agents have beenfound useful: arginine hydrochloride, sodium thiocyanate, ammoniumthiocyanate, ammonium sulfate, ammonium chloride, calcium chloride, zincchloride, or sodium acetate. The teaching of US 20150071925, herebyincorporated herein as if fully stated. Organic esters may also beuseful. See US 20150071925, hereby incorporated herein as if fullystated.

Effective amounts are used.

Anti-Caking Agents

Anti-Caking Agents are particularly useful where the drug active isadded separately from the firm former composition in powder orparticulate form.

Moisture, pressure and temperature all adversely affect powdered andgranulated products. These conditions can make products cake, lump,bridge, clog equipment and cause fib and performance problems.Anti-caking and Free-flow powder agents can improve the flow behaviorand storage stability of a broad variety of food products.

Silica derived materials are preferred.

A non limitative list includes: tricalcium phosphate, powderedcellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide,potassium ferrocyanide, calcium ferrocyanide, bone phosphate, sodiumsilicate, silicon dioxide, calcium silicate, magnesium trisilicate,talcum powder, sodium aluminosilicate, potassium aluminium silicate,calcium aluminosilicate, bentonite, aluminium silicate, stearic acid,and polydimethylsiloxane.

Effective amounts are employed for reliable flow of powder/particulate.

Pharmaceutical Actives (also Referred to Herein as Active PharmaceuticalIngredients or Drugs)

By the term pharmaceutical active agent, we mean a drug as describedbelow. By pharmaceutical active agent composition, we mean anycomposition containing one or more pharmaceutical active agents.However, it is expressly contemplated that the compositions and methodstaught herein are not limited to drugs but may include any active agentas more fully described below.

The active agents that may be incorporated into the films of the presentinvention include, without limitation bioactive agents such aspharmaceutical active agents, cosmetic active agents, drugs,medicaments, botanicals, antigens or allergens such as ragweed pollen,spores, microorganisms, plant actives, enzymes and vitamins, as wellasother active agents such as seeds, mouthwash components, flavors,fragrances, preservatives, sweetening agents, colorants, spices, andcombinations thereof. An active agent composition is a compositioncontaining one or more of the active agents described herein.

A wide variety of non-limiting medicaments, bioactive active substancesand pharmaceutical compositions may be included in the dosage forms ofthe present invention.

Examples of useful drugs include ace-inhibitors, antianginal drugs,anti-arrhythmias, anti-asthmatics, anti-cholesterolemics, analgesics,anesthetics, anti-convulsants, anti-depressants, anti-diabetic agents,anti-diarrhea preparations, antidotes, anti-histamines,anti-hypertensive drugs, anti-inflammatory agents, anti-lipid agents,anti-manics, anti-nauseants, anti-stroke agents, anti-thyroidpreparations, anti-tumor drugs, anti-viral agents, acne drugs,alkaloids, amino acid preparations, anti-tussives, anti-uricemic drugs,anti-viral drugs, anabolic preparations, systemic and non-systemicanti-infective agents, anti-neoplastics, anti-parkinsonian agents,anti-rheumatic agents, appetite stimulants, biological responsemodifiers, blood modifiers, bone metabolism regulators, cardiovascularagents, central nervous system stimulates, cholinesterase inhibitors,contraceptives, decongestants, dietary supplements, dopamine receptoragonists, endometriosis management agents, enzymes, erectile dysfunctiontherapies, fertility agents, gastrointestinal agents, homeopathicremedies, hormones, hypercalcemia and hypocalcemia management agents,immunomodulators, immunosuppressives, migraine preparations, motionsickness treatments, muscle relaxants, obesity management agents,osteoporosis preparations, oxytocics, parasympatholytics,parasympathomimetics, prostaglandins, psychotherapeutic agents,respiratory agents, sedatives, smoking cessation aids, sympatholytics,tremor preparations, urinary tract agents, vasodilators, laxatives,antacids, ion exchange resins, anti-pyretics, appetite suppressants,expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflammatorysubstances, coronary dilators, cerebral dilators, peripheralvasodilators, psycho-tropics, stimulants, anti-hypertensive drugs,vasoconstrictors, migraine treatments, antibiotics, tranquilizers,anti-psychotics, anti-tumor drugs, anti-coagulants, anti-thromboticdrugs, hypnotics, anti-emetics, anti-nauseants, anti-convulsants,neuromuscular drugs, hyper- and hypo-glycemic agents, thyroid andanti-thyroid preparations, diuretics, anti-spasmodics, uterinerelaxants, anti-obesity drugs, erythropoietic drugs, anti-asthmatics,cough suppressants, mucolytics, DNA and genetic modifying drugs, andcombinations thereof.

Examples of medicating active ingredients contemplated for use in thepresent invention include antacids, Hz-antagonists, and analgesics. Forexample, antacid dosages can be prepared using the ingredients calciumcarbonate alone or in combination with magnesium hydroxide, and/oraluminum hydroxide. Moreover, antacids can be used in combination withHz-antagonists.

Analgesics include opiates and opiate derivatives, such as oxycodone(available as Oxycontin.®), ibuprofen, aspirin, acetaminophen, andcombinations thereof that may optionally include caffeine.

Other preferred drugs for other preferred active ingredients for use inthe present invention include anti-diarrheals such as immodium AD,anti-histamines, anti-tussives, decongestants, vitamins, and breathfresheners. Common drugs used alone or in combination for colds, pain,fever, cough, congestion, runny nose and allergies, such asacetaminophen, chlorpheniramine maleate, dextromethorphan,pseudoephedrine HCl and diphenhydramine may be included in the filmcompositions of the present invention.

Also contemplated for use herein are anxiolytics such as alprazolam(available as Xanax.®); anti-psychotics such as clozopin (available asClozaril.®) and haloperidol (available as Haldol.®); non-steroidalanti-inflammatories (NSAID's) such as dicyclofenacs (available asVoltaren.®) and etodolac (available as Lodine.®), anti-histamines suchas loratadine (available as Claritin.®), astemizole (available asHismanal.™), nabumetone (available as Relafen.®), and Clemastine(available as Tavist.®); anti-emetics such as granisetron hydrochloride(available as Kytril.®) and nabilone (available as Cesamet.™);bronchodilators such as Bentolin.®, albuterol sulfate (available asProventil.®); anti-depressants such as fluoxetine hydrochloride(available as Prozac.®), sertraline hydrochloride (available asZoloft.®), and paroxtine hydrochloride (available as Paxil.®);anti-migraines such as Imigra.®, ACE-inhibitors such as enalaprilat(available as Vasotec.®), captopril (available as Capoten.®) andlisinopril (available as Zestril.®); anti-Alzheimer's agents, such asnicergoline; and Ca.sup.H-antagonists such as nifedipine (available asProcardia.® and Adalat.®), and verapamil hydrochloride (available asCalan.®).

Erectile dysfunction therapies include, but are not limited to, drugsfor facilitating blood flow to the penis, and for effecting autonomicnervous activities, such as increasing parasympathetic (cholinergic) anddecreasing sympathetic (adrenersic) activities. Useful non-limitingdrugs include sildenafils, such as Viagra.®, tadalafils, such asCialis.®, vardenafils, apomorphines, such as Uprima.®, yohimbinehydrochlorides such as Aphrodyne.®, and alprostadils such as Caverject.®.

The popular Hz-antagonists which are contemplated for use in the presentinvention include cimetidine, ranitidine hydrochloride, famotidine,nizatidien, ebrotidine, mifentidine, roxatidine, pisatidine andaceroxatidine.

Active antacid ingredients include, but are not limited to, thefollowing: aluminum hydroxide, dihydroxyaluminum aminoacetate,aminoacetic acid, aluminum phosphate, dihydroxyaluminum sodiumcarbonate, bicarbonate, bismuth aluminate, bismuth carbonate, bismuthsubcarbonate, bismuth subgallate, bismuth subnitrate, bismuth subsilysilate, calcium carbonate, calcium phosphate, citrate ion (acid orsalt), amino acetic acid, hydrate magnesium aluminate sulfate,magaldrate, magnesium aluminosilicate, magnesium carbonate, magnesiumglycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate,milk solids, aluminum mono-ordibasic calcium phosphate, tricalciumphosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate,magnesium aluminosilicates, tartaric acids and salts.

The pharmaceutically active agents employed in the present invention mayinclude allergens or antigens, such as, but not limited to, plantpollens from grasses, trees, or ragweed; animal danders, which are tinyscales shed from the skin and hair of cats and other furred animals;insects, such as house dust mites, bees, and wasps; and drugs, such aspenicillin.

Botanicals may be employed, including marijuana, tobacco and anyderivative thereof, including tetrahydrocannabinol and cannabidiol).Such botanicals may or may not be approved for pharmaceutical use orotherwise understood to be pharmaceutically active.

An anti-oxidant may also be added to the film to prevent the degradationof an active, especially where the active is photosensitive.

Cosmetic active agents may include breath freshening compounds likementhol, other flavors or fragrances, especially those used for oralhygiene, as well as actives used in dental and oral cleansing such asquaternary ammonium bases. The effect of flavors may be enhanced usingflavor enhancers like tartaric acid, citric acid, vanillin, or the like.Anti-tartar agents for dental use may also be employed.

Coloring Agents

Also color additives can be used in preparing the films. Such coloradditives include food, drug and cosmetic colors (FD&C), drug andcosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C).These colors are dyes, their corresponding lakes, and certain naturaland derived colorants. Lakes are dyes absorbed on aluminum hydroxide.

Other examples of coloring agents include known azo dyes, organic orinorganic pigments, or coloring agents of natural origin. Inorganicpigments are preferred, such as the oxides or iron or titanium, theseoxides, being added in concentrations ranging from about 0.001 to about10%, and preferably about 0.5 to about 3%, based on the weight of allthe components.

Flavors

Flavors may be chosen from natural and synthetic flavoring liquids. Anillustrative list of such agents includes volatile oils, syntheticflavor oils, flavoring aromatics, oils, liquids, oleoresins or extractsderived from plants, leaves, flowers, fruits, stems and combinationsthereof. A non-limiting representative list of examples includes mintoils, cocoa, and citrus oils such as lemon, orange, grape, lime andgrapefruit and fruit essences including apple, pear, peach, grape,strawberry, raspberry, cherry, plum, pineapple, apricot or other fruitflavors.

The films containing flavorings may be added to provide a hot or coldflavored drink or soup.

These flavorings include, without limitation, tea and soup flavoringssuch as beef and chicken.

Other useful flavorings include aldehydes and esters such asbenzaldehyde (cherry, almond), citral i.e., alphacitral (lemon, lime),neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon),aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehydeC-12 (citrus fruits), tolyl aldehyde (cherry, almond),2,6-dimethyloctanol (green fruit), and 2-dodecenal (citrus, mandarin),combinations thereof and the like.

The sweeteners may be chosen from the following non-limiting list:glucose (corn syrup), dextrose, invert sugar, fructose, and combinationsthereof; saccharin and its various salts such as the sodium salt;dipeptide sweeteners such as aspartame; dihydrochalcone compounds,glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives ofsucrose such as sucralose; sugar alcohols such as sorbitol, mannitol,xylitol, and the like. Also contemplated are hydrogenated starchhydrolysates and the synthetic sweetener3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide,particularly the potassium salt (acesulfame-K), and sodium and calciumsalts thereof, and natural intensive sweeteners, such as Lo Han Kuo.Other sweeteners may also be used.

When the active is combined with the polymer in the solvent, the type ofmatrix that is formed depends on the solubilities of the active and thepolymer. If the active and/or polymer are soluble in the selectedsolvent, this may form a solution. However, if the components are notsoluble, the matrix may be classified as an emulsion, a colloid, or asuspension.

Transdermal Films

In certain embodiments, the deposit method of the present invention maybe used to make transdermal films. Since transdermal films are typicallymultilayer, different layers may be deposited in series, if necessarybetween drying intervals. Backing layers of materials not readilydepositable may be inserted into the mold or well (including inter aliamicroneedles). The following patents, describing transdermalcompositions, are incorporated by reference as if fully stated herein(including incorpations into such patents) U.S. Pat. No. 9,089,527 2(assigned to Lohmann); U.S. Pat. No. 8,696,637 (assigned to Lohmann);U.S. Pat. No.6,117,448 (assigned to Lohmann); U.S. Pat. No. 5,820,876(assigned to Lohmann). Obviously, different compositions, and excipientsare used in transdermal systems from oral soluble films and so theteaching of the incorporate patents is important for such embodiments.

EXAMPLES

A number of template molds were made, 10 mil recess thick, and adheredto a Teflon sheet. The compositions are shown in Table 1A, and Table 2Aand Table 3. Results after deposit and drying for the compositions ofTable 1A and Table 2A, are found in Tables 1B and 2B, respectively.

As the results in Table 1B demonstrate, the compositions described inTable 1A were generally too viscous and exhibited too much surfacetension to adequately flow into a mold.

A number of the examples of 2A successfully flowed into films, andcertain examples demonstrated good embedding of solids. For example,sample D of Table 2A showed good embedding of calcium carbonateparticulate, which was used as a “dummy” drug particulate. Theflowability of these examples would preclude their ability to be coatedusing conventional wet casting techniques. Their very proclivity to flowwould lead them to roll off the substrate in a conventional castingprocess.

The compositions of Table 3 are non-aqueous. Sample NA4, comprising29.7% PEO (300,000) and 70.3% PEG400 is a promising approach for a slowrelease film of the present invention.

Applicants observed that a range of 20-40% PEO (300,000 mw and above),together with PEG 80 as a solvent may be an attractive formulationoption where slow release is desired from a film made by the depositmethod.

TABLE 1A Aqueous Evaluation Samples Sample HPMC HPMC ID Instagel CornStarch K15M F50 HPC PVP PG PEG2000 1 1.45% 1.99% 2 9.15% 3 4.32% 6.81%4.48% 8.16% 4 3.74% 5.79% 2.23% 6.83% 5 2.57% 1.05% 6   5% 7 1.25% 81.00% 9 1.86% 10 0.90%

TABLE 1B Aqueous Evaluation Samples Post Thermal Treatment Sample IDPass Fail Cause 1 x high contact angle on silicon mold, did not wet orspread, did not embed solids, does not disperse in water 2 x highcontact angle on silicon mold, did not wet or spread, did not embedsolids, does not disperse in water 3 x too viscous 4 x very viscous,produced thick film that did not disperse readily in water 5 x film verythin and brittle, poor wetting and spreading on substrate, strongadhesion to teflon substrate when dried 6 x too viscous 7 x film toobrittle and too thin 8 x film too brittle and too thin 9 x too viscousto add to template 10 x too viscous to add to template

TABLE 2A Aqueous PEO Film Former Compositions Sample ID PEO 100K PEO300K PEO 900K PEG400 PG PS 20 Viscosity cps A 9.09% 18.18% B 10.58%6.68% 331* C 10.59% 7.30% 366* D 10.69% 5.59% 306* E 4.76% F 6.52%12.90% 1.65% G 5.71% 3.50% 2243-1261** H 5.79% 4.05% I 18.31% 7.44%1846-1155** J 18.31% 8.80% K 12.38% 4.45% 413* L 10.53% 5.61% M 7.06%1.77% 5.60% N 4.76% 653-468** O 3.67% 217* P 6.28% *Newtonian fluidviscosity **Non-Newtonian fluid viscosity range from 10 to 100 s⁻¹

TABLE 2B Aqueous PEO Film Former Post Thermal Treatment EvaluationsSample ID Pass Fail Cause A x films .2 mm think easily disperse in waterB x good spreading and wetting, low viscosity C x good spreading andwetting, low viscosity D x film former added to calcium carbonate, goodembedding of solids E x viscous, but good spreading and wetting, thinfilm easily disperses in water F x viscous, films .15 mm, easilydisperse in water G x x viscous composition, can produce good thin film,readily dispersible in water H x x viscous composition, can produce goodfilm, easily dispersible in water I x too viscous, thick film, noteasily dispersible in water J x too viscous, thick film, not easilydispersible in water K x good spreading and wetting, low viscosity L xgood spreading and wetting, low viscosity M x good spreading andwetting, low viscosity N x produced film with good dissolution in waterO x produced thin film with good dissolution in water P x produced thinfilm easily dispersible in water

TABLE 3 Non-Aqueous PEO Compositions Post Thermal Treatment 90° C.Sample ID PEO100K PEO300K PEG400 Pass Fail Cause NA1 8.88% 91.12% xlacks cohesion, waxy dispersion NA2 9.51% 90.49% x lacks cohesion, waxydispersion NA3 10.22% 89.78% x weak, wet, thick (1.23 mm) and fragilefilm; poor dissoution in water NA4 29.70% 70.30% x x viscous dispersion,poor flowability, opaque thick (1.6 mm) strong film; slow dissolution inwater, tacky vehicle when wet

TABLE 4 Examples of Surface Tension Values Temp □ ° C. mN/m Water 2571.97 40 69.56 80 62.6 PEG200 20 43.5 ISP 25 23Example of a Jelly Dosage form in a numbered pouch

In this example, ½ tsp of Welch's Reduced Sugar Concord Grape Jelly wasset aside. 10 mg of diazepam, sourced from Fagron, was set aside. TheJelly and diazepam where mixed until they appeared uniformly mixed. Themixture was observed at one and two hour time points, and at each timepoint it appeared that the drug remained uniformly distributed. Themixture was placed in an aluminum food pouch and sealed with a HeathrowScientific Heat Sealer. The resulting pouch was numbered using apermanent marker as “1-001”. After twelve hours, the pouch was openedwith a scissors and taken orally by a health adult male. The product wasdetermined to have acceptable organoleptic properties and mouthfeel.Inspection of the pouch after ingestion confirmed little residue inpouch, confirming complete administration of the intended dose.

Example of a Gelatin Format

A pre-made strawberry gelatin manufactured by Con Agra foods waspurchased. The ingredient listing was as follows: water, less than 2%of: fruit juice from concentrate, carrageenan, adipic acid, citric acid,potassium citrate, carob bean gum, natural flavor, sodium citrate,sucralose, salt, natural and artificial flavor, xantham gum, yellow 6and Red 40. Diazepam from Fagron was placed into the gelatin using asyringe to into the center of the gelatin. The resulting product wassampled by a healthy adult male who noted excellent taste and mouthfeel.

Example of the Rheology of a firm Jell-O or Gelatin Composition.

FIGS. 10 and 11 measure the same material; FIG. 11 has data pointssampled for reference. Tropical Gelatin Dessert was purchased from thesupermarket — a ready-made dessert. G′>>G″—linear viscoelasticsubstance. This shows a very small phase angle.

FIG. 12 shows the phase angle and the tan (delta) values from FIGS. 10and 11 .

Example of a Jam Base

Here is an example of the properties of the outer shell for example,similar “jam” like sticky substance:

.5 rad/s, Strain = .0015 tan(delta) Weak Gel 1.109 Weak Gel 1.025 WeakGel 1.018 Emulsion 1.142 Emulsion 1.056

FIGS. 13 and 14 show the outer rheology of Smuckers Strawberry Jam.

What is claimed is:
 1. An oral soluble film containing at least oneactive agent, the oral soluble film being made by a method comprisingcontinuously stirring an emulsion of a film forming composition and atleast one active agent in a tank; depositing the emulsion separatelyinto each of a plurality of wells while continuously stirring theemulsion in the tank, the emulsion of the film forming composition andthe at least one active agent forming a contact angle with the well ofless than 90.degrees, wherein the emulsion flows into a film in the wellwithin 20 seconds; and drying the film using hot air currents to formthe oral soluble film containing the at least one active agent.
 2. Theoral soluble film according to claim 1, wherein the film is formed inthe well without mechanical intervention.
 3. The oral soluble filmaccording to claim 1, wherein the at least one active agent comprises abotanical.
 4. The oral soluble film according to claim 1, wherein the atleast one active agent comprises a botanical and the oral soluble filmfurther comprises a bitter masking agent.
 5. The oral soluble filmaccording to claim 1, wherein the at least one active agent comprisesderivative of a botanical
 6. The oral soluble film according to claim 1,wherein the at least one active agent comprises a derivative ofmarijuana. The oral soluble film according to claim 1, wherein the wellis shaped to form three dimensional attributes on the bottom of thefilm.